This study used fMRI on awake rats to investigate the neural response to capsaicin-induced pain. Capsaicin was injected into the hindpaw of wild-type rats and TRPV1 knockout rats. Wild-type rats showed activation of brain regions involved in the pain pathway, emotion, and memory after capsaicin injection. TRPV1 knockout rats did not show this same activation pattern in response to capsaicin. However, formalin still activated pain regions in TRPV1 knockout rats. The results suggest capsaicin may have antinociceptive effects independent of TRPV1 signaling and that imaging pain responses in awake animals can provide insights into full pain perception.
This study examined hormone responses of the hypothalamic-pituitary-adrenal (HPA) axis to nicotine and mecamylamine in an in vitro model, using tissues from rats that underwent continuous nicotine administration and withdrawal. The results suggest that in vitro HPA responses are enhanced and sustained following continuous nicotine administration, but reduced following nicotine withdrawal. Additionally, tissue responses to mecamylamine were enhanced after continuous nicotine, resulting in decreased hormone release, but not during nicotine withdrawal. These findings contrast with the authors' previous in vivo studies, possibly due to removal of suprahypothalamic influences or dilution of nicotine concentrations in the in vitro system. Further studies are needed to better
Respiration in Anesthetized Mice: Evidence-Based Recommendations for Improved...InsideScientific
Join Dr. James Marx as he discusses improving the care and use of mice in biomedical research, with a focus on the pharmacology behind the effects of anesthetics on respiration.
Essentially, all anesthetic drugs suppress respiration in animals. This fact, combined with the high metabolic rate of mice, means that monitoring and respiratory support are critical for ensuring successful anesthesia of mice. Unfortunately, the monitoring and support for anesthetized mice lags well behind the care we give our other species. Recent publications and advances in equipment have given us the opportunity to make significant improvements in the care we provide anesthetized mice.
In this talk, Dr. Marx will briefly discuss the pharmacology behind the effects of anesthetics on respiration. He will then use evidence-based medicine to give practical recommendations for monitoring and support of respiration. An important part of this will include discussing normal physiologic values for respiratory parameters and highlighting differences between anesthetics and their effects on respiration. The recommendations in this discussion will be based on evidence of treatable or preventable issues. Lastly, he will briefly discuss technologies which are commonly used in other species and may be applied in mice in the near future.
Key Topics Include:
- The significant effects of anesthesia on respiration in mice
- Practical methods of monitoring and providing support to anesthetized mice
- Discussing equipment that will provide valuable information while addressing the depth of anesthesia in mice
Clinical Results and Mechanisms of MAGCELL®-Therapy in Chemotherapy-Induced P...Mary Fickling
Electrode-free electrotherapy also known as MAGCELL®-therapy, arrived in the UK and Ireland in 2017 via exclusive distributors PhysioPod® UK Limited. This article, explains the clinical results and mechanism of MAGCELL® MICROCIRC in CIPN with scientific references.
MAGCELL® MICROCIRC can positively influence symptoms of neurotoxicities like sensory ataxia, neuropathy and neuropathic pain symptoms (especially CIPN I-IV) on hands and feet as a result of chemotherapy. Moreover a significant increase in nerve conductivity speed (ulnar nerve) was achieved by the treatment. Sufferers are now able to apply this effective treatment at home via the personal unit, due to repeatable short-treatment periods, no side effects and even through textile (including shoes).
This study investigated the effects of repeated deep brain stimulation of the pedunculopontine tegmental nucleus (PPTg) in rats. Electrodes were implanted in the PPTg of rats which then received 6 days of stimulation. Behavioral responses and neural activation markers cFOS and GAP-43 were assessed on days 1 and 6. Results found that repeated stimulation increased the threshold current needed to elicit behavioral responses on day 6 compared to day 1, suggesting an inhibitory effect. Expression of cFOS and GAP-43 was also found near the stimulation site, indicating repeated stimulation triggers neural plasticity.
This study tested the hypothesis that combining increased intrinsic growth ability through PTEN deletion with reduced extrinsic growth inhibition through Nogo deletion may further improve axonal regeneration after spinal cord injury compared to manipulating either factor alone. The results showed that PTEN/Nogo codeletion enhanced corticospinal tract regeneration more than PTEN deletion alone but did not further increase sprouting compared to PTEN deletion. While regeneration and sprouting increased in PTEN-deleted and PTEN/Nogo-deleted mice, functional recovery was only temporarily improved or not improved, indicating additional strategies are needed to translate enhanced axonal growth into functional benefits.
Functional Ultrasound (fUS) Imaging in the Brain of Awake Behaving MiceInsideScientific
To watch the webinar, visit:
https://insidescientific.com/webinar/functional-ultrasound-imaging-brain-awake-behaving-mice-neurotar-iconeus
Functional ultrasound (fUS) imaging is a new kid on the block in neuroimaging. It combines high spaciotemporal resolution with deep tissue penetration, which enables non-invasive whole-brain imaging in mice.
This exciting new technology complements and extends classical imaging modalities: it enables more straightforward, unobstructed and non-invasive functional measurements in mouse models of CNS diseases. Sensitive to changes in cerebral blood volume, fUS imaging is used to characterize brain networks with functional connectivity analysis and to measure the responses to sensory stimuli and pharmacological challenges.
fUS imaging performed in the brain of awake mice removes the biases and artifacts associated with the use of general anesthesia, which is no longer a “necessary evil” of translational imaging. Besides that: fUS imaging in awake mice allows integrating functional imaging with behavioral readouts starting from open field locomotion tracking to maze navigation and sociability studies.
In this webinar, you will learn:
– Functional ultrasound (fUS) imaging methodology
– How translational fUS neuroimaging helps to advance basic neuroscience research and preclinical drug discovery
– The main advantages and limitations of using functional ultrasound compared to other techniques such as BOLD fMRI
– The benefits of imaging in awake, head-restrained but otherwise freely moving mice
– Imaging functional activation, connectivity and pharmacologically-induced changes in awake and behaving mice
– How to combine fUS imaging with behavioral observation
- Rats underwent fear conditioning experiments with electrodes implanted in brain regions involved in fear processing. They were exposed to conditioned stimuli (tones) paired or unpaired with shocks over multiple days.
- During training, rats showed similar freezing levels to both paired (CS+) and unpaired (CS-) tones. Over extinction sessions, rats learned to extinguish their fear response to the unpaired tone more quickly than the paired tone.
- Recordings were made from the brain regions throughout training and extinction. Future analysis will examine neural oscillations in these areas correlated with fear behaviors. This may provide insight into emotional processing circuits related to psychiatric disorders.
Electrophysiology of Human Native Receptors in Neurological and Mental DisordersInsideScientific
Dr. Agenor Limon presents research integrating functional metrics with large anatomical, transcriptomic, and proteomic datasets to evaluate the relationship between synaptic E/I ratio and behavioral abnormalities across postmortem intervals and brain banks.
Alterations in synaptic function have been found in transcriptomic, genetic, and proteomic studies of neurological and mental disorders. Clinical and preclinical studies suggest that synaptic dysfunction and behavioral abnormalities in disorders like Alzheimer’s disease and schizophrenia may be mechanistically linked to the emergence of imbalances between excitatory (E) and inhibitory (I) receptors. However, until recently, the electrophysiological E/I synaptic ratio had only been measured in animal models.
Using pioneering methods developed in the lab including reactivation and microtransplantation of synaptic receptors from frozen human brains, Dr. Agenor Limon’s research team has obtained electrophysiological metrics of global synaptic E/I ratios in cortical brain regions of subjects that were affected by Alzheimer’s Disease and synaptic measurements in schizophrenia.
In this webinar, Dr. Agenor Limon will present recent research integrating functional metrics with large anatomical, transcriptomic, and proteomic datasets to evaluate the relationship between synaptic E/I ratio and behavioral abnormalities across postmortem intervals and brain banks.
Key Topics Include:
- Understand the global synaptic excitation to inhibition ratio between excitatory and inhibitory synaptic receptors determined from reactivated frozen human brain tissue
- Understand the relationship between electrophysiological metrics of receptor function and multi-omic data in neurodegenerative disorders
- Understand the role of deviations of the excitation to inhibition ratio with clinical presentation in Alzheimer’s disease
This study examined hormone responses of the hypothalamic-pituitary-adrenal (HPA) axis to nicotine and mecamylamine in an in vitro model, using tissues from rats that underwent continuous nicotine administration and withdrawal. The results suggest that in vitro HPA responses are enhanced and sustained following continuous nicotine administration, but reduced following nicotine withdrawal. Additionally, tissue responses to mecamylamine were enhanced after continuous nicotine, resulting in decreased hormone release, but not during nicotine withdrawal. These findings contrast with the authors' previous in vivo studies, possibly due to removal of suprahypothalamic influences or dilution of nicotine concentrations in the in vitro system. Further studies are needed to better
Respiration in Anesthetized Mice: Evidence-Based Recommendations for Improved...InsideScientific
Join Dr. James Marx as he discusses improving the care and use of mice in biomedical research, with a focus on the pharmacology behind the effects of anesthetics on respiration.
Essentially, all anesthetic drugs suppress respiration in animals. This fact, combined with the high metabolic rate of mice, means that monitoring and respiratory support are critical for ensuring successful anesthesia of mice. Unfortunately, the monitoring and support for anesthetized mice lags well behind the care we give our other species. Recent publications and advances in equipment have given us the opportunity to make significant improvements in the care we provide anesthetized mice.
In this talk, Dr. Marx will briefly discuss the pharmacology behind the effects of anesthetics on respiration. He will then use evidence-based medicine to give practical recommendations for monitoring and support of respiration. An important part of this will include discussing normal physiologic values for respiratory parameters and highlighting differences between anesthetics and their effects on respiration. The recommendations in this discussion will be based on evidence of treatable or preventable issues. Lastly, he will briefly discuss technologies which are commonly used in other species and may be applied in mice in the near future.
Key Topics Include:
- The significant effects of anesthesia on respiration in mice
- Practical methods of monitoring and providing support to anesthetized mice
- Discussing equipment that will provide valuable information while addressing the depth of anesthesia in mice
Clinical Results and Mechanisms of MAGCELL®-Therapy in Chemotherapy-Induced P...Mary Fickling
Electrode-free electrotherapy also known as MAGCELL®-therapy, arrived in the UK and Ireland in 2017 via exclusive distributors PhysioPod® UK Limited. This article, explains the clinical results and mechanism of MAGCELL® MICROCIRC in CIPN with scientific references.
MAGCELL® MICROCIRC can positively influence symptoms of neurotoxicities like sensory ataxia, neuropathy and neuropathic pain symptoms (especially CIPN I-IV) on hands and feet as a result of chemotherapy. Moreover a significant increase in nerve conductivity speed (ulnar nerve) was achieved by the treatment. Sufferers are now able to apply this effective treatment at home via the personal unit, due to repeatable short-treatment periods, no side effects and even through textile (including shoes).
This study investigated the effects of repeated deep brain stimulation of the pedunculopontine tegmental nucleus (PPTg) in rats. Electrodes were implanted in the PPTg of rats which then received 6 days of stimulation. Behavioral responses and neural activation markers cFOS and GAP-43 were assessed on days 1 and 6. Results found that repeated stimulation increased the threshold current needed to elicit behavioral responses on day 6 compared to day 1, suggesting an inhibitory effect. Expression of cFOS and GAP-43 was also found near the stimulation site, indicating repeated stimulation triggers neural plasticity.
This study tested the hypothesis that combining increased intrinsic growth ability through PTEN deletion with reduced extrinsic growth inhibition through Nogo deletion may further improve axonal regeneration after spinal cord injury compared to manipulating either factor alone. The results showed that PTEN/Nogo codeletion enhanced corticospinal tract regeneration more than PTEN deletion alone but did not further increase sprouting compared to PTEN deletion. While regeneration and sprouting increased in PTEN-deleted and PTEN/Nogo-deleted mice, functional recovery was only temporarily improved or not improved, indicating additional strategies are needed to translate enhanced axonal growth into functional benefits.
Functional Ultrasound (fUS) Imaging in the Brain of Awake Behaving MiceInsideScientific
To watch the webinar, visit:
https://insidescientific.com/webinar/functional-ultrasound-imaging-brain-awake-behaving-mice-neurotar-iconeus
Functional ultrasound (fUS) imaging is a new kid on the block in neuroimaging. It combines high spaciotemporal resolution with deep tissue penetration, which enables non-invasive whole-brain imaging in mice.
This exciting new technology complements and extends classical imaging modalities: it enables more straightforward, unobstructed and non-invasive functional measurements in mouse models of CNS diseases. Sensitive to changes in cerebral blood volume, fUS imaging is used to characterize brain networks with functional connectivity analysis and to measure the responses to sensory stimuli and pharmacological challenges.
fUS imaging performed in the brain of awake mice removes the biases and artifacts associated with the use of general anesthesia, which is no longer a “necessary evil” of translational imaging. Besides that: fUS imaging in awake mice allows integrating functional imaging with behavioral readouts starting from open field locomotion tracking to maze navigation and sociability studies.
In this webinar, you will learn:
– Functional ultrasound (fUS) imaging methodology
– How translational fUS neuroimaging helps to advance basic neuroscience research and preclinical drug discovery
– The main advantages and limitations of using functional ultrasound compared to other techniques such as BOLD fMRI
– The benefits of imaging in awake, head-restrained but otherwise freely moving mice
– Imaging functional activation, connectivity and pharmacologically-induced changes in awake and behaving mice
– How to combine fUS imaging with behavioral observation
- Rats underwent fear conditioning experiments with electrodes implanted in brain regions involved in fear processing. They were exposed to conditioned stimuli (tones) paired or unpaired with shocks over multiple days.
- During training, rats showed similar freezing levels to both paired (CS+) and unpaired (CS-) tones. Over extinction sessions, rats learned to extinguish their fear response to the unpaired tone more quickly than the paired tone.
- Recordings were made from the brain regions throughout training and extinction. Future analysis will examine neural oscillations in these areas correlated with fear behaviors. This may provide insight into emotional processing circuits related to psychiatric disorders.
Electrophysiology of Human Native Receptors in Neurological and Mental DisordersInsideScientific
Dr. Agenor Limon presents research integrating functional metrics with large anatomical, transcriptomic, and proteomic datasets to evaluate the relationship between synaptic E/I ratio and behavioral abnormalities across postmortem intervals and brain banks.
Alterations in synaptic function have been found in transcriptomic, genetic, and proteomic studies of neurological and mental disorders. Clinical and preclinical studies suggest that synaptic dysfunction and behavioral abnormalities in disorders like Alzheimer’s disease and schizophrenia may be mechanistically linked to the emergence of imbalances between excitatory (E) and inhibitory (I) receptors. However, until recently, the electrophysiological E/I synaptic ratio had only been measured in animal models.
Using pioneering methods developed in the lab including reactivation and microtransplantation of synaptic receptors from frozen human brains, Dr. Agenor Limon’s research team has obtained electrophysiological metrics of global synaptic E/I ratios in cortical brain regions of subjects that were affected by Alzheimer’s Disease and synaptic measurements in schizophrenia.
In this webinar, Dr. Agenor Limon will present recent research integrating functional metrics with large anatomical, transcriptomic, and proteomic datasets to evaluate the relationship between synaptic E/I ratio and behavioral abnormalities across postmortem intervals and brain banks.
Key Topics Include:
- Understand the global synaptic excitation to inhibition ratio between excitatory and inhibitory synaptic receptors determined from reactivated frozen human brain tissue
- Understand the relationship between electrophysiological metrics of receptor function and multi-omic data in neurodegenerative disorders
- Understand the role of deviations of the excitation to inhibition ratio with clinical presentation in Alzheimer’s disease
This document summarizes experiments exploring the neuroprotective effects of progranulin in two models of environmental neurotoxicity: PC12 cells exposed to MPTP and mice exposed to BSSG. In PC12 cells, progranulin protected against cell death induced by the neurotoxin MPTP. In mice, BSSG exposure induced gait disturbances and locomotor changes that were partially attenuated by progranulin treatment via lentiviral delivery, though muscle strength was not affected. Further studies are needed to better understand the mechanisms and long-term effects of progranulin neuroprotection in these models.
The longer the delay between the appearance of the first symptoms of Hansen’s Disease and the start of treatment, the more likely it is for nerve damage to occur
The document summarizes a study that investigated whether neurodegeneration alone can cause schizophrenia-like behaviors in mice. The study ablated neural stem cells in transgenic mice using ganciclovir over 56 days. Behavioral tests revealed no significant differences between control and ablated mice in prepulse inhibition, locomotor activity after PCP/amphetamine, time spent in open arms of elevated plus maze, or floating behavior in Porsolt swim test. This suggests neurodegeneration alone may not cause schizophrenia. However, other studies that also applied stressors found ablation did produce schizophrenia-like behaviors, so stress may be a contributing factor.
Studying Epilepsy in Awake Head-Fixed Mice Using Microscopy, Electrophysiolog...InsideScientific
Epilepsy research employs sophisticated research methods such as fluorescence optical imaging and optogenetics, as well as novel electrophysiological techniques, to address unresolved questions about seizure generation and propagation on the cellular and circuitry levels. Since epilepsy research is most relevant when performed in non-anesthetized mice, it requires specialized tools that ensure stable head fixation during high-precision imaging and recordings.
In this webinar, Dr. Anthony Umpierre (Prof. LongJun Wu group, Mayo Clinic, USA) and Prof. Rob Wykes (UCL, UK) present their research on microglial calcium signaling and epileptic networks carried out in awake head-fixed mice. In addition to sharing exciting new findings, the presenters address the challenges of working with awake mice.
Key topics will include…
- Mesoscopic investigations of seizure dynamics and propagation using widefield calcium imaging
- Generating full-bandwidth electrophysiological recordings enabled by graphene micro-transistors to detect spreading depolarizations and seizures
- On-demand optogenetic induction of spreading depolarizations to investigate pharmacological suppression in the awake brain
- The impact of acute versus chronic window preparations on microglial calcium activity
- The use of genetically encoded calcium indicators to study calcium dynamics in microglia
- The effects of bi-directional shifts in neuronal activity caused by kainate-triggered status epilepticus and isoflurane anesthesia on microglial calcium
This study proposes a novel two-drug therapeutic strategy for treating traumatic brain injury (TBI) using human chorionic gonadotropin (hCG) and erythropoietin (EPO). hCG is administered first to increase the number of neural stem cells after injury, then EPO is given to promote their differentiation into new neurons. Prior studies support that this combination improves behavioral outcomes and reduces lesion volumes in animal models of TBI more than either drug alone. The current study tests this two-drug approach in a rat fluid percussion injury model, finding it reduces neurological deficits, cortical damage, and hippocampal cell loss compared to controls. The strategy shows promise for translation to clinical treatment of TBI.
This study assessed sub-chronic neuropathological and biochemical changes in the mouse visual system 3 weeks after repetitive mild traumatic brain injury (r-mTBI). Histological analysis found increased cellularity and areas of demyelination in the optic nerves of r-mTBI mice compared to repetitive sham controls. The number of retinal ganglion cells was also decreased by about 25% in r-mTBI mice. Proteomic analysis of optic nerves showed changes indicating effects on neuronal processes like microtubule depolymerization and filament disassembly. Lipidomic analysis found changes in phospholipid species, including an increase in lysophosphatidylcholine, a demyelinating agent. The results indicate
EEG and Telemetry: Best Practices for Managing Large Data Sets to Investigate...InsideScientific
In this webinar sponsored by Data Sciences International, Dr. Marcio Furtado presents his research highlighting the importance of anomalous EEG detection to study experimental epilepsy and assess the efficacy of potential anticonvulsants and neuroprotectants. He also discusses why continuous EEG monitoring at a high sampling rate is critical to properly detect seizures and how to effectively deal with large telemetry data sets.
Watch this webinar to learn:
- Why neural hyper-synchronization (seizure activity) can result in permanent brain damage
- Tips for organizing, standardizing, and batch processing large data sets
- What features can be extracted from large EEG data sets
- Why inadequate sampling rates can lead to signal aliasing and how to avoid it
- How telemetry can be used to continuously monitor EEG and assess seizure activity in animal models of epilepsy
Sensorimotor Network Development During Early Postnatal Life in the Awake and...InsideScientific
In the last decades, electrophysiological and imaging-based approaches provided significant new insights into the mechanisms of neuronal development. Nevertheless, many important questions remain unanswered. How does the fine control of a motor output develop? How does sensorimotor integration in the early and subsequent phases of brain development shape behavior? How does sensorimotor development evolve in awake and sleeping states? What role do myoclonic twitches play in this process?
Answering these questions requires performing high-precision tests in the brain of non-anesthetized animals across sleep and wake during the early stages of their postnatal development. Such tests require head-fixation apparatus suitable for neonatal and juvenile rodents. The Mobile HomeCage combines a stable head-fixation with an air-lifted cage that closely resembles laboratory rodents’ natural habitat – an optimal platform for studying early postnatal brain development.
In this webinar, Dr. Cavaccini (Prof. Karayannis’s lab at the Brain Research Institute, University of Zurich) and Dr. Dooley (Prof. Blumberg’s lab at the University of Iowa), share their insights into the development of rodent sensorimotor neuronal circuits during early postnatal life. They elucidate the cortical and subcortical mechanisms involved in the development of sensorimotor circuitry during wakefulness (in a mouse model) and REM sleep (in a rat model).
Key Takeaways
Dr. Anna Cavaccini:
- Anatomical and functional changes occur at the striatal level before and after the onset of different sensory modalities
- Locomotor activity changes throughout early development, and it correlates with striatal function
- Sensory information coming from whiskers affects locomotion and striatal function before and after the onset of different sensory modalities
Dr. James Dooley:
- Myoclonic twitches in REM sleep continue to trigger cortical and thalamic activity beyond the early postnatal period
- Twitch-related thalamic activity is spatiotemporally refined by the third postnatal week
- Motor thalamus activity reflects an internal model of movement produced by twitches and is dependent on the cerebellar output
Aton et al., Neuron, 2009 - Mechanisms of Sleep-Dependent Consolidation of Co...SaraAton
This study investigated the cellular mechanisms involved in sleep-dependent consolidation of ocular dominance plasticity (ODP), a form of cortical plasticity triggered by monocular deprivation. The study found that:
1) Sleep consolidates ODP primarily by strengthening responses to stimulation of the non-deprived eye.
2) Consolidation is inhibited by reversible intracortical antagonism of NMDA receptors or cAMP-dependent protein kinase during post-deprivation sleep.
3) Consolidation is associated with sleep-dependent increases in neuronal activity in visual cortex and phosphorylation of proteins required for glutamatergic synapse potentiation.
This demonstrates that synaptic strengthening via NMDA receptor and
This document summarizes a study that investigated whether melatonin treatment could modify depression-like and anxiety-like behaviors in a mouse model of seasonal affective disorder (SAD). Mice were exposed to short photoperiods to induce SAD-like behaviors and symptoms. Daily melatonin injections before lights off altered the expression patterns of circadian clock genes in the suprachiasmatic nucleus and genes related to serotonin neurotransmission in the dorsal raphe. Melatonin treatment also reduced depression-like behavior in forced swim tests. While melatonin did not strongly phase shift circadian rhythms, it increased the amplitude of oscillations in clock gene expression. The findings suggest modest adjustments to circadian rhythms from melat
Scientists have developed a new drug called intracellular sigma peptide (ISP) that shows promise in helping treat paralysis by encouraging nerves in the spinal cord to grow and repair injuries. In lab animals with severe spinal injuries, ISP helped recover abilities like urinating, moving muscles, or both. While more work remains, scientists are hopeful ISP may provide a future therapy for humans to regain lost functions from spinal cord injuries.
The Brain as a Whole: Executive Neurons and Sustaining Homeostatic GliaInsideScientific
Carl Petersen and Alexei Verkhratsky share their research on homeostatic neuroglia and imaging of neuronal network function. This webinar is brought to you by APS’ new journal, Function, and part of their Physiology in Focus learning series.
During this exclusive live webinar, Carl Petersen and Alexei Verkhratsky discuss astrocyte-mediated homeostatic control of the central nervous system, and how optical and 2-photon microscopy can be used for functional neuroimaging.
Imaging Neuronal Function
Carl Petersen, PhD
Highly dynamic and spatially distributed neuronal circuits in the brain control mammalian behavior. Through technological advances, optical measurements of neuronal function can now be carried out in behaving mice at multiple scales. Wide-field imaging allows the dynamic interactions between different brain areas to be studied as sensory information is processed and transformed into behavioral output. Within a brain region, two-photon microscopy can be used to image the neuronal network activity with cellular resolution allowing different types of projection neurons to be distinguished. Together optical methods provide versatile tools for causal mechanistic understanding of neuronal network function in mice.
Astrocytes: indispensable neuronal supporters in sickness and in health
Alexei Verkhratsky, MD, PhD, DSc
The nervous system is composed of two arms: the executive neurons and the homeostatic neuroglia. The neurons require energy, support, and protection, all of which is provided by the neuroglia. Astrocytes, the principal homeostatic cells of the brain and spinal cord, are tightly integrated into the neural networks and act within the context of the neural tissue. As astrocytes control the homeostasis of the central nervous system at all levels of organization, from the molecular to the whole organ level, we can begin to define and understand brain vulnerabilities to aging and diseases.
Ikrar Et Al (Cell Type Specific Regulation Of Cortical Excitability Through T...Taruna Ikrar
This study investigated using the allatostatin receptor (AlstR) system to selectively inhibit neuronal activity in specific cell types in the cortex. The researchers expressed AlstRs in either excitatory or inhibitory neurons in mouse brain slices using Cre-driven expression. They found that applying the allatostatin peptide ligand strongly reduced spiking in AlstR-expressing neurons but not others. When targeting excitatory neurons, it constrained activity propagation, but enhancing it when targeting inhibitory neurons. Expressing AlstRs in excitatory neurons also effectively suppressed induced seizure activity. This work demonstrates the AlstR system can regulate cortical excitability in a cell-type specific manner.
This study investigated the effects of transplanting neural stem cells (NSCs) into the brains of Alzheimer's disease (AD) rats. NSCs were harvested from embryonic rat hippocampus and transplanted into the hippocampus of AD rats. Protein levels were measured in the hippocampus of control, AD, and NSC-transplanted rats using proteomics. Expression of choline acetyltransferase, heat shock proteins, and cytoskeletal proteins was higher in the NSC group compared to the AD group. Expression of astrocyte markers GFAP and S100β was lower in the NSC group. This suggests NSCs may generate new neural cells to relieve damage to the cholinergic system and resist apoptosis in AD rats.
Harnessing EEG Methods to Improve Basic and Translational Research for CNS Di...InsideScientific
In this webinar, Dr. Robert Gould, Assistant Professor of Physiology and Pharmacology at Wake Forest School of Medicine, discusses how EEG can be used to study sleep architecture and arousal, addiction/substance use disorder, schizophrenia and drug discovery.
Michael Girand, Scientific Applications Manager at DSI, conveys a holistic approach when studying CNS-based applications and discusses how researchers can improve their study design and get more endpoints out of the animal model.
Key discussion topics include:
- Multiple translational applications of EEG to enhance your research
- Highlighting sleep disruptions across CNS disorders
- Understanding how to apply EEG to measure changes in brain function
- Tools available to create a robust study design
- The collaborative approach between technologies, scientists, and DSI
1) Neural stem cells cultured in vitro with epidermal growth factor and basic fibroblast growth factor proliferated and formed neurospheres. 2) Addition of PPARγ agonists like ciglitazone and 15d-PGJ2 inhibited neural stem cell proliferation in a dose-dependent manner. 3) Interestingly, neural stem cells cultured with PPARγ agonists showed increased expression of oligodendrocyte markers and a reduction in the neural stem cell marker nestin, indicating promotion of oligodendrocyte differentiation.
The document discusses various newer neuromodulation methods for treating psychiatric disorders such as magnetic seizure therapy, transcranial alternating current stimulation, transcranial random noise stimulation, optogenetics, thermal stimulation, auricular stimulation, trigeminal nerve stimulation, transcranial ultrasound, and chemical stimulation. It provides details on the mechanisms of each method and reviews evidence from human and animal studies. Applications for several of these newer neuromodulation methods in clinical settings like depression, schizophrenia, cognitive enhancement, pain, and epilepsy are also mentioned.
1) Deletion of the SCN1A gene in GABAergic interneurons mediated by the Dlx5,6Cre locus leads to increased susceptibility to seizures induced by pentylenetetrazol (PTZ) in mice, including shorter latency to seizures, longer duration of seizures, and increased fatality.
2) Preliminary analysis found an association between increased attenuation of EEG waves after seizures and sudden unexpected death in epilepsy (SUDEP) in a Dravet syndrome mouse model, suggesting EEG attenuation could be a predictive biomarker for SUDEP risk.
3) The study aims to further compare the Dravet syndrome mouse model to a focal cortical dysplasia model to examine shared physiological biomarkers and mechanisms of
Next-generation small molecule neuro regeneration therapy
Dual actions of increasing endogenous stem cells and
suppressing glial differentiation of neural stem cells to
regenerate neurons by peripheral administration of low
molecular weight compounds.
Next-generation small molecule neuro regeneration therapy
Dual actions of increasing endogenous stem cells and suppressing glial differentiation of neural stem cells to regenerate neurons by peripheral administration of low molecular weight compounds.
Next-generation hair regenerative medicine
Hair regrowth by a low molecular weight compound that stimulates the proliferation of hair follicle stem cells.
Este documento describe las técnicas, procesos e instrumentos del coaching. Entre las técnicas se incluyen exposiciones grupales, lluvia de ideas y juegos de cualidades. Los instrumentos del coaching incluyen el desarrollo de habilidades y la motivación. El proceso de coaching generalmente implica analizar la situación actual, establecer objetivos, identificar barreras y desarrollar un plan de acción con seguimiento.
This document summarizes experiments exploring the neuroprotective effects of progranulin in two models of environmental neurotoxicity: PC12 cells exposed to MPTP and mice exposed to BSSG. In PC12 cells, progranulin protected against cell death induced by the neurotoxin MPTP. In mice, BSSG exposure induced gait disturbances and locomotor changes that were partially attenuated by progranulin treatment via lentiviral delivery, though muscle strength was not affected. Further studies are needed to better understand the mechanisms and long-term effects of progranulin neuroprotection in these models.
The longer the delay between the appearance of the first symptoms of Hansen’s Disease and the start of treatment, the more likely it is for nerve damage to occur
The document summarizes a study that investigated whether neurodegeneration alone can cause schizophrenia-like behaviors in mice. The study ablated neural stem cells in transgenic mice using ganciclovir over 56 days. Behavioral tests revealed no significant differences between control and ablated mice in prepulse inhibition, locomotor activity after PCP/amphetamine, time spent in open arms of elevated plus maze, or floating behavior in Porsolt swim test. This suggests neurodegeneration alone may not cause schizophrenia. However, other studies that also applied stressors found ablation did produce schizophrenia-like behaviors, so stress may be a contributing factor.
Studying Epilepsy in Awake Head-Fixed Mice Using Microscopy, Electrophysiolog...InsideScientific
Epilepsy research employs sophisticated research methods such as fluorescence optical imaging and optogenetics, as well as novel electrophysiological techniques, to address unresolved questions about seizure generation and propagation on the cellular and circuitry levels. Since epilepsy research is most relevant when performed in non-anesthetized mice, it requires specialized tools that ensure stable head fixation during high-precision imaging and recordings.
In this webinar, Dr. Anthony Umpierre (Prof. LongJun Wu group, Mayo Clinic, USA) and Prof. Rob Wykes (UCL, UK) present their research on microglial calcium signaling and epileptic networks carried out in awake head-fixed mice. In addition to sharing exciting new findings, the presenters address the challenges of working with awake mice.
Key topics will include…
- Mesoscopic investigations of seizure dynamics and propagation using widefield calcium imaging
- Generating full-bandwidth electrophysiological recordings enabled by graphene micro-transistors to detect spreading depolarizations and seizures
- On-demand optogenetic induction of spreading depolarizations to investigate pharmacological suppression in the awake brain
- The impact of acute versus chronic window preparations on microglial calcium activity
- The use of genetically encoded calcium indicators to study calcium dynamics in microglia
- The effects of bi-directional shifts in neuronal activity caused by kainate-triggered status epilepticus and isoflurane anesthesia on microglial calcium
This study proposes a novel two-drug therapeutic strategy for treating traumatic brain injury (TBI) using human chorionic gonadotropin (hCG) and erythropoietin (EPO). hCG is administered first to increase the number of neural stem cells after injury, then EPO is given to promote their differentiation into new neurons. Prior studies support that this combination improves behavioral outcomes and reduces lesion volumes in animal models of TBI more than either drug alone. The current study tests this two-drug approach in a rat fluid percussion injury model, finding it reduces neurological deficits, cortical damage, and hippocampal cell loss compared to controls. The strategy shows promise for translation to clinical treatment of TBI.
This study assessed sub-chronic neuropathological and biochemical changes in the mouse visual system 3 weeks after repetitive mild traumatic brain injury (r-mTBI). Histological analysis found increased cellularity and areas of demyelination in the optic nerves of r-mTBI mice compared to repetitive sham controls. The number of retinal ganglion cells was also decreased by about 25% in r-mTBI mice. Proteomic analysis of optic nerves showed changes indicating effects on neuronal processes like microtubule depolymerization and filament disassembly. Lipidomic analysis found changes in phospholipid species, including an increase in lysophosphatidylcholine, a demyelinating agent. The results indicate
EEG and Telemetry: Best Practices for Managing Large Data Sets to Investigate...InsideScientific
In this webinar sponsored by Data Sciences International, Dr. Marcio Furtado presents his research highlighting the importance of anomalous EEG detection to study experimental epilepsy and assess the efficacy of potential anticonvulsants and neuroprotectants. He also discusses why continuous EEG monitoring at a high sampling rate is critical to properly detect seizures and how to effectively deal with large telemetry data sets.
Watch this webinar to learn:
- Why neural hyper-synchronization (seizure activity) can result in permanent brain damage
- Tips for organizing, standardizing, and batch processing large data sets
- What features can be extracted from large EEG data sets
- Why inadequate sampling rates can lead to signal aliasing and how to avoid it
- How telemetry can be used to continuously monitor EEG and assess seizure activity in animal models of epilepsy
Sensorimotor Network Development During Early Postnatal Life in the Awake and...InsideScientific
In the last decades, electrophysiological and imaging-based approaches provided significant new insights into the mechanisms of neuronal development. Nevertheless, many important questions remain unanswered. How does the fine control of a motor output develop? How does sensorimotor integration in the early and subsequent phases of brain development shape behavior? How does sensorimotor development evolve in awake and sleeping states? What role do myoclonic twitches play in this process?
Answering these questions requires performing high-precision tests in the brain of non-anesthetized animals across sleep and wake during the early stages of their postnatal development. Such tests require head-fixation apparatus suitable for neonatal and juvenile rodents. The Mobile HomeCage combines a stable head-fixation with an air-lifted cage that closely resembles laboratory rodents’ natural habitat – an optimal platform for studying early postnatal brain development.
In this webinar, Dr. Cavaccini (Prof. Karayannis’s lab at the Brain Research Institute, University of Zurich) and Dr. Dooley (Prof. Blumberg’s lab at the University of Iowa), share their insights into the development of rodent sensorimotor neuronal circuits during early postnatal life. They elucidate the cortical and subcortical mechanisms involved in the development of sensorimotor circuitry during wakefulness (in a mouse model) and REM sleep (in a rat model).
Key Takeaways
Dr. Anna Cavaccini:
- Anatomical and functional changes occur at the striatal level before and after the onset of different sensory modalities
- Locomotor activity changes throughout early development, and it correlates with striatal function
- Sensory information coming from whiskers affects locomotion and striatal function before and after the onset of different sensory modalities
Dr. James Dooley:
- Myoclonic twitches in REM sleep continue to trigger cortical and thalamic activity beyond the early postnatal period
- Twitch-related thalamic activity is spatiotemporally refined by the third postnatal week
- Motor thalamus activity reflects an internal model of movement produced by twitches and is dependent on the cerebellar output
Aton et al., Neuron, 2009 - Mechanisms of Sleep-Dependent Consolidation of Co...SaraAton
This study investigated the cellular mechanisms involved in sleep-dependent consolidation of ocular dominance plasticity (ODP), a form of cortical plasticity triggered by monocular deprivation. The study found that:
1) Sleep consolidates ODP primarily by strengthening responses to stimulation of the non-deprived eye.
2) Consolidation is inhibited by reversible intracortical antagonism of NMDA receptors or cAMP-dependent protein kinase during post-deprivation sleep.
3) Consolidation is associated with sleep-dependent increases in neuronal activity in visual cortex and phosphorylation of proteins required for glutamatergic synapse potentiation.
This demonstrates that synaptic strengthening via NMDA receptor and
This document summarizes a study that investigated whether melatonin treatment could modify depression-like and anxiety-like behaviors in a mouse model of seasonal affective disorder (SAD). Mice were exposed to short photoperiods to induce SAD-like behaviors and symptoms. Daily melatonin injections before lights off altered the expression patterns of circadian clock genes in the suprachiasmatic nucleus and genes related to serotonin neurotransmission in the dorsal raphe. Melatonin treatment also reduced depression-like behavior in forced swim tests. While melatonin did not strongly phase shift circadian rhythms, it increased the amplitude of oscillations in clock gene expression. The findings suggest modest adjustments to circadian rhythms from melat
Scientists have developed a new drug called intracellular sigma peptide (ISP) that shows promise in helping treat paralysis by encouraging nerves in the spinal cord to grow and repair injuries. In lab animals with severe spinal injuries, ISP helped recover abilities like urinating, moving muscles, or both. While more work remains, scientists are hopeful ISP may provide a future therapy for humans to regain lost functions from spinal cord injuries.
The Brain as a Whole: Executive Neurons and Sustaining Homeostatic GliaInsideScientific
Carl Petersen and Alexei Verkhratsky share their research on homeostatic neuroglia and imaging of neuronal network function. This webinar is brought to you by APS’ new journal, Function, and part of their Physiology in Focus learning series.
During this exclusive live webinar, Carl Petersen and Alexei Verkhratsky discuss astrocyte-mediated homeostatic control of the central nervous system, and how optical and 2-photon microscopy can be used for functional neuroimaging.
Imaging Neuronal Function
Carl Petersen, PhD
Highly dynamic and spatially distributed neuronal circuits in the brain control mammalian behavior. Through technological advances, optical measurements of neuronal function can now be carried out in behaving mice at multiple scales. Wide-field imaging allows the dynamic interactions between different brain areas to be studied as sensory information is processed and transformed into behavioral output. Within a brain region, two-photon microscopy can be used to image the neuronal network activity with cellular resolution allowing different types of projection neurons to be distinguished. Together optical methods provide versatile tools for causal mechanistic understanding of neuronal network function in mice.
Astrocytes: indispensable neuronal supporters in sickness and in health
Alexei Verkhratsky, MD, PhD, DSc
The nervous system is composed of two arms: the executive neurons and the homeostatic neuroglia. The neurons require energy, support, and protection, all of which is provided by the neuroglia. Astrocytes, the principal homeostatic cells of the brain and spinal cord, are tightly integrated into the neural networks and act within the context of the neural tissue. As astrocytes control the homeostasis of the central nervous system at all levels of organization, from the molecular to the whole organ level, we can begin to define and understand brain vulnerabilities to aging and diseases.
Ikrar Et Al (Cell Type Specific Regulation Of Cortical Excitability Through T...Taruna Ikrar
This study investigated using the allatostatin receptor (AlstR) system to selectively inhibit neuronal activity in specific cell types in the cortex. The researchers expressed AlstRs in either excitatory or inhibitory neurons in mouse brain slices using Cre-driven expression. They found that applying the allatostatin peptide ligand strongly reduced spiking in AlstR-expressing neurons but not others. When targeting excitatory neurons, it constrained activity propagation, but enhancing it when targeting inhibitory neurons. Expressing AlstRs in excitatory neurons also effectively suppressed induced seizure activity. This work demonstrates the AlstR system can regulate cortical excitability in a cell-type specific manner.
This study investigated the effects of transplanting neural stem cells (NSCs) into the brains of Alzheimer's disease (AD) rats. NSCs were harvested from embryonic rat hippocampus and transplanted into the hippocampus of AD rats. Protein levels were measured in the hippocampus of control, AD, and NSC-transplanted rats using proteomics. Expression of choline acetyltransferase, heat shock proteins, and cytoskeletal proteins was higher in the NSC group compared to the AD group. Expression of astrocyte markers GFAP and S100β was lower in the NSC group. This suggests NSCs may generate new neural cells to relieve damage to the cholinergic system and resist apoptosis in AD rats.
Harnessing EEG Methods to Improve Basic and Translational Research for CNS Di...InsideScientific
In this webinar, Dr. Robert Gould, Assistant Professor of Physiology and Pharmacology at Wake Forest School of Medicine, discusses how EEG can be used to study sleep architecture and arousal, addiction/substance use disorder, schizophrenia and drug discovery.
Michael Girand, Scientific Applications Manager at DSI, conveys a holistic approach when studying CNS-based applications and discusses how researchers can improve their study design and get more endpoints out of the animal model.
Key discussion topics include:
- Multiple translational applications of EEG to enhance your research
- Highlighting sleep disruptions across CNS disorders
- Understanding how to apply EEG to measure changes in brain function
- Tools available to create a robust study design
- The collaborative approach between technologies, scientists, and DSI
1) Neural stem cells cultured in vitro with epidermal growth factor and basic fibroblast growth factor proliferated and formed neurospheres. 2) Addition of PPARγ agonists like ciglitazone and 15d-PGJ2 inhibited neural stem cell proliferation in a dose-dependent manner. 3) Interestingly, neural stem cells cultured with PPARγ agonists showed increased expression of oligodendrocyte markers and a reduction in the neural stem cell marker nestin, indicating promotion of oligodendrocyte differentiation.
The document discusses various newer neuromodulation methods for treating psychiatric disorders such as magnetic seizure therapy, transcranial alternating current stimulation, transcranial random noise stimulation, optogenetics, thermal stimulation, auricular stimulation, trigeminal nerve stimulation, transcranial ultrasound, and chemical stimulation. It provides details on the mechanisms of each method and reviews evidence from human and animal studies. Applications for several of these newer neuromodulation methods in clinical settings like depression, schizophrenia, cognitive enhancement, pain, and epilepsy are also mentioned.
1) Deletion of the SCN1A gene in GABAergic interneurons mediated by the Dlx5,6Cre locus leads to increased susceptibility to seizures induced by pentylenetetrazol (PTZ) in mice, including shorter latency to seizures, longer duration of seizures, and increased fatality.
2) Preliminary analysis found an association between increased attenuation of EEG waves after seizures and sudden unexpected death in epilepsy (SUDEP) in a Dravet syndrome mouse model, suggesting EEG attenuation could be a predictive biomarker for SUDEP risk.
3) The study aims to further compare the Dravet syndrome mouse model to a focal cortical dysplasia model to examine shared physiological biomarkers and mechanisms of
Next-generation small molecule neuro regeneration therapy
Dual actions of increasing endogenous stem cells and
suppressing glial differentiation of neural stem cells to
regenerate neurons by peripheral administration of low
molecular weight compounds.
Next-generation small molecule neuro regeneration therapy
Dual actions of increasing endogenous stem cells and suppressing glial differentiation of neural stem cells to regenerate neurons by peripheral administration of low molecular weight compounds.
Next-generation hair regenerative medicine
Hair regrowth by a low molecular weight compound that stimulates the proliferation of hair follicle stem cells.
Este documento describe las técnicas, procesos e instrumentos del coaching. Entre las técnicas se incluyen exposiciones grupales, lluvia de ideas y juegos de cualidades. Los instrumentos del coaching incluyen el desarrollo de habilidades y la motivación. El proceso de coaching generalmente implica analizar la situación actual, establecer objetivos, identificar barreras y desarrollar un plan de acción con seguimiento.
Saia perfil del emprendedor emprendedores_marialeMaria Contreras
El documento describe las características de un emprendedor y lo que se requiere para un emprendimiento exitoso. Un emprendedor es alguien que está dispuesto a asumir riesgos al iniciar proyectos nuevos y difíciles que requieren esfuerzo, tiempo y dinero. Los emprendedores y los emprendimientos van de la mano para construir nuevos proyectos.
The document summarizes the stages of prenatal development from conception through the third trimester of pregnancy. It describes the germinal stage beginning with conception and fertilization, the embryonic stage of implantation and cell differentiation, and the fetal stage where body systems continue developing. It also discusses potential genetic problems like Down syndrome and inherited diseases, as well as environmental risks from maternal drug use, disease, and other factors that can negatively impact the developing fetus. An approximate timetable provides details of physical changes and milestones for each month of the three trimesters of pregnancy.
The document discusses how untreated and undiagnosed mental health issues in parents and children hurt families. Approximately one in five adults in the US experiences mental illness in a given year, equating to over 2.7 million adults in Florida alone. However, many children and parents do not receive needed treatment. This can negatively impact children's well-being and development. It also increases families' involvement with the child welfare and juvenile justice systems. The current approach in these systems focuses on short-term case management rather than long-term treatment, which is what is needed to effectively address underlying mental health and substance abuse issues. Moving to a treatment-based model that provides comprehensive, family-focused support could help keep more families together
ESP block - future direction and remaining questionsAmit Pawa
This Talk was delivered by Dr Pawa on 5th June 2021 as part of the ISURA 2021 hybrid conference held in Toronto.
The Future Direction of this block and remaining questions to be answered are covered here
Temporal-Spatial Expressions of Spy1 in Rat Sciatic Nerve After CrushJiao Yang
1. The study examined the expression of the cell cycle protein Spy1 in a rat sciatic nerve crush injury model over time.
2. Spy1 expression was found to gradually increase after injury, peaking at day 3, due to increased expression in both axons and Schwann cells.
3. Spy1 expression correlated with Schwann cell proliferation after injury and Spy1 was found to localize in axons in the injured segment but did not co-localize with the growth protein GAP43.
This study investigated the effects of developmental exposure to the organophosphate chlorpyrifos on social play behavior and endocannabinoid system activation in rats. The researchers found that rats exposed to chlorpyrifos engaged in more social play behaviors compared to controls. However, chlorpyrifos exposure did not affect phosphorylation of cannabinoid receptors in brain regions involved in social play, suggesting that increased social play is not related to changes in endocannabinoid system activation. While endocannabinoid signaling may play a role in altered social behavior, chlorpyrifos may induce changes in other neurotransmitter systems like dopamine that are important for social play.
This study examined functional connectivity of the medial temporal lobe (MTL) and its relation to learning and awareness. Participants completed a sensory learning task and were classified as AWARE or UNAWARE based on their ability to learn tone-visual stimulus associations. For AWARE participants, MTL activity correlated with learned discrimination and reversal, engaging dorsolateral prefrontal and occipital cortices. For UNAWARE participants, MTL activity correlated only with simple facilitation and engaged contralateral MTL, thalamus regions. This suggests the MTL contribution to learning depends on its pattern of interactions with other brain regions.
Edgardo J. Arroyo is an Associate Research Scientist at Yale University School of Medicine who has extensive experience researching various aspects of myelin formation, degradation, and regeneration in the central and peripheral nervous systems. His research has focused on elucidating the cellular mechanisms and microanatomy of neuron-glial interactions using techniques such as immunohistochemistry, confocal microscopy, and biochemistry. He has studied topics such as the effects of spinal cord injury, stem cell transplantation, sodium channel expression after nerve damage, and how demyelination affects the molecular organization of nodes of Ranvier.
The document discusses three studies that examined the effects of multimodal early onset stimulation (MEOS) therapy in patients and rats with severe brain injuries. The studies found that MEOS therapy combined with an enriched environment:
1) Led to improvements in vegetative parameters and motor functions in some comatose patients.
2) Resulted in reduced brain lesion volumes and enhanced recovery of motor functions in rats.
3) Provided additional benefits over enriched environment alone, including better reversal of motor and cognitive dysfunction in rats.
Don't Miss a Beat: Understanding Continuous, Real Time Physiologic MonitoringInsideScientific
In vivo, preclinical research encompasses numerous study designs with various species and endpoints being monitored. Having access to all available study data allows the scientist to comprehensively understand the study paradigm and make informed research decisions. During Session 3 of our webseries "Biotelemetry For The Life Sciences", presenters discussed the importance of continuous, real-time monitoring in preclinical research. Case studies included using EEG as a biomarker for CNS activity and drug discovery and using telemetry for disease characterizations and and evaluation of vaccines in Biodefense research.
During this exclusive webinar sponsored by Data Sciences International, Steve Fox shares his experience from pharmaceutical development; discussing the importance of continuous EEG monitoring for sleep studies. Anna Honko explains the importance of having access to real-time, continuous data when studying infectious diseases in non-human primates in a Biodefense setting. In addition, Dusty Sarazan reviews how and why continuous, real-time monitoring has become a preferred and essential method for acquiring and studying physiology in today's preclinical research setting.
Key Topics:
EEG as a biomarker for CNS activity and a platform for pre-clincal drug discovery
Sleep/wake patterns and rhythms, and how qEEG signatures allow for accurate clinical predictions of efficacy and CNS adverse event screening
Considering the FDA Animal Rule
Basic disease characterizations and evaluation of vaccines and therapeutics
Non-human primate models of viral biodefense and emerging pathogens
Translating pre-clinical study findings to human, clinical populations
Guest Speakers:
Steve Fox, BS
Associate Principal Scientist,
Merck & Co., Inc.
Anna Honko, PhD
Staff Scientist,
NIH/NIAID Integrated Research Facility
R. Dustan Sarazan, DVM, PhD
Vice President & Chief Scientific Officer, Data Sciences International
Transcranial Magnetic Stimulation ( TMS) for Chronic PainDr. Rafael Higashi
Aula sobre avanço no tratamento da dor crônica com o uso de Estimulação Magnética Transcraniana (EMT) ministrada por Dr. Rafael Higashi, médico neurologista, no departamento de tratamento da dor do Centro Médico da Universidade de Nova York, NYU, EUA.
www.estimulacaoneurologica.com.br
Corticolimbic anatomic characteristics predetermine risk for chronic pain.Paul Coelho, MD
1) The study longitudinally tracked brain properties in subacute back pain patients for 3 years to determine if certain brain characteristics predisposed patients to developing chronic pain or recovering.
2) They found that higher incidence of white matter and functional connections within the dorsal medial prefrontal cortex–amygdala–accumbens circuit, as well as smaller amygdala volume, were independent risk factors that accounted for 60% of the variance in determining if a patient's pain would become chronic.
3) Opioid gene polymorphisms and negative mood contributed indirectly to the risk of chronic pain through their effects on these corticolimbic anatomical factors.
1. The study aims to evaluate how distinct neuron populations in the thalamus and motor cortex contribute to learning skilled motor tasks in rodents.
2. Rats were trained on a forelimb reaching task and then received injections targeting the thalamocortical pathway to selectively eliminate those neurons.
3. Post-surgery, the rats' performance on the reaching task was assessed and compared to pre-surgery to analyze the functional role of the thalamocortical pathway in motor learning and skilled reaching behaviors.
1) C. elegans raised in social environments displayed stronger neural activity, as evidenced by more numerous, intense, and larger synapses compared to C. elegans raised in isolation.
2) Behavioral assays also showed C. elegans from social environments had higher response rates to external stimuli and more thrashes per minute than isolated C. elegans.
3) These results support the hypothesis that more social stimulation leads to increased neural plasticity and synaptic strength in C. elegans.
1. The study examined the relationship between endogenous opioid system tone and regional brain activity related to pain processing in fibromyalgia patients. Specifically, it compared resting m-opioid receptor availability measured with PET imaging to brain activation during evoked pain assessed with fMRI.
2. The results showed that in antinociceptive brain regions like the dorsolateral prefrontal cortex and anterior cingulate cortex, reduced m-opioid receptor availability was associated with decreased brain activity during pain stimulation. Reduced receptor availability was also linked to lower activation in the nucleus accumbens and lower ratings of clinical affective pain.
3. This is the first study to directly link endogenous opioid system dysfunction to abnormal brain responses to
This study evaluated the neuroprotective effects of hypothermia (HT) treatment compared to normothermia (NT) in a rodent model of neonatal hypoxic-ischemic injury (HII). The results showed that HT-treated animals had less weight loss, faster neurological recovery as measured by righting reflex, smaller lesions on MRI, and reduced lesion severity scores compared to NT animals. HT treatment also decreased the volume of irreversible "core" injury tissue while increasing the volume of potentially salvageable "penumbra" tissue. These findings suggest that HT has significant neuroprotective effects in neonatal HII by reducing injury and improving outcomes.
This study investigated combining deep brain stimulation (DBS), PTEN suppression, and Schwann cell transplantation as a treatment for spinal cord injury in rats. Rats received either DBS, PTEN suppression via AAV-shPTEN injection, or a combination of both, along with Schwann cell transplantation at the injury site. Locomotor activity was assessed over 8 weeks and showed no significant differences between groups. Preliminary immunohistochemistry results found that the combination of PTEN suppression and DBS resulted in higher volumes of white matter and serotonin compared to other groups. This suggests the combined approach may produce better tissue repair than individual methods alone. Further studies are needed to confirm these findings.
This study examined sex differences in the anxiolytic effects of diazepam and parvalbumin-positive GABA neurons in trait anxiety Long Evans rats. The following were found:
1) Male rats bred for high anxiety showed greater anxiolytic response to diazepam compared to females as measured by open arm time in the elevated plus maze.
2) Immunohistochemical analysis found differences in parvalbumin-positive GABA neurons between brain regions and sex/anxiety groups. Males had more neurons in the central amygdala while females had more in the caudate putamen.
3) Differences were also seen in the hippocampus, with trait anxiety linked to differences regardless of sex
"The Future of Sleep with Neurotechnology" - Anant Sachetee (Rythm)Hyper Wellbeing
"The Future of Sleep with Neurotechnology" - Anant Sachetee (Rythm)
Delivered at the inaugural Hyper Wellbeing Summit, 14th November 2016, Mountain View, California.
For more information including details of subsequent events, please visit http://hyperwellbeing.com
The summit was created to foster a community around an emerging industry - Wellness as a Service (WaaS). Consumer technologies, in particular wearables and mobile, are powering a consumer revolution. A revolution to turn health and wellness into platform delivered services. A revolution enabling consumer data-driven disease risk reduction. A revolution extending health care past sick care towards consumer-led lifelong health, wellness and lifestyle optimization.
WaaS newsletter sign-up http://eepurl.com/b71fdr
@hyperwellbeing
Passive avoidance training decreases synapse density in the hippocampus of domestic chicks. The study found that 6 hours after training chicks to avoid pecking at a bead coated in a bitter substance, the density of synapses in the dorsal and ventral hippocampus was lower compared to untrained control chicks. By 24 hours post-training, this difference was no longer present. A hemispheric asymmetry was also observed, with some regions showing enhanced synapse density in the left hemisphere for water-trained chicks but in the right hemisphere for methyl anthranilate-trained chicks. The results suggest that passive avoidance learning and stress can prune synapses in the chick hippocampus.
A NALYSIS OF P AIN H EMODYNAMIC R ESPONSE U SING N EAR -I NFRARED S PECTROSCOPYijma
Despite recent advances in brain research, understa
nding the various signals for pain and pain intensi
ties
in the brain cortex is still a complex task due to
temporal and spatial variations of brain haemodynam
ics.
In this paper we have investigated pain based on ce
rebral hemodynamics via near-infrared spectroscopy
(NIRS). This study presents a pain stimulation expe
riment that uses three acupuncture manipulation
techniques to safely induce pain in healthy subject
s. Acupuncture pain response was presented and
Haemodynamic pain signal analysis showed the presence of dominant channels and their relationship
among surrounding channels, which contribute the fu
rther pain research area.
A NALYSIS OF P AIN H EMODYNAMIC R ESPONSE U SING N EAR -I NFRARED S PECTROSCOPY
fnsys-09-00015
1. ORIGINAL RESEARCH ARTICLE
published: 19 February 2015
doi: 10.3389/fnsys.2015.00015
Identifying the integrated neural networks involved in
capsaicin-induced pain using fMRI in awake TRPV1
knockout and wild-type rats
Jason R. Yee1
, William Kenkel1
, John C. Caccaviello1
, Kevin Gamber2
, Phil Simmons2
,
Mark Nedelman3
, Praveen Kulkarni1
and Craig F. Ferris1
*
1
Center for Translational NeuroImaging, Department of Psychology, Northeastern University, Boston, MA, USA
2
SAGE Labs, St Louis, MO, USA
3
Ekam Imaging, Boston, MA, USA
Edited by:
Mikhail Lebedev, Duke University,
USA
Reviewed by:
Yen-Yu Ian Shih, University of North
Carolina at Chapel Hill, USA
Mark D. Meadowcroft, The
Pennsylvania State University, USA
Chih-Cheng Chen, Academia Sinica,
Taiwan
*Correspondence:
Craig F. Ferris, Center for
Translational NeuroImaging,
Department of Psychology,
Northeastern University, Boston,
MA 02115-5000, USA
e-mail: c.ferris@neu.edu
In the present study, we used functional MRI in awake rats to investigate the pain
response that accompanies intradermal injection of capsaicin into the hindpaw. To
this end, we used BOLD imaging together with a 3D segmented, annotated rat
atlas and computational analysis to identify the integrated neural circuits involved in
capsaicin-induced pain. The specificity of the pain response to capsaicin was tested
in a transgenic model that contains a biallelic deletion of the gene encoding for the
transient receptor potential cation channel subfamily V member 1 (TRPV1). Capsaicin is
an exogenous ligand for the TRPV1 receptor, and in wild-type rats, activated the putative
pain neural circuit. In addition, capsaicin-treated wild-type rats exhibited activation in brain
regions comprising the Papez circuit and habenular system, systems that play important
roles in the integration of emotional information, and learning and memory of aversive
information, respectively. As expected, capsaicin administration to TRPV1-KO rats failed
to elicit the robust BOLD activation pattern observed in wild-type controls. However,
the intradermal injection of formalin elicited a significant activation of the putative pain
pathway as represented by such areas as the anterior cingulate, somatosensory cortex,
parabrachial nucleus, and periaqueductal gray. Notably, comparison of neural responses
to capsaicin in wild-type vs. knock-out rats uncovered evidence that capsaicin may
function in an antinociceptive capacity independent of TRPV1 signaling. Our data suggest
that neuroimaging of pain in awake, conscious animals has the potential to inform the
neurobiological basis of full and integrated perceptions of pain.
Keywords: capsaicin, TRPV1, fMRI BOLD, fMRI methods, habenula, Papez circuit, pain networks
INTRODUCTION
The transient receptor potential vanilloid 1 (TRPV1) channel
is a polymodal receptor critical to the sensing of noxious heat
(>43◦C), bidirectional changes in pH, and capsaicin, amongst
a variety of other stimuli (Szallasi et al., 2007). Capsaicin, a
pharmacologically active agent found in chili peppers, causes
burning and itching sensation due to binding at the TRPV1
receptor, and subsequent activation of polymodal C and A-delta
nociceptive fibers (Caterina et al., 1997, 2000; Tominaga et al.,
1998). Acutely, TRPV1 activation with peripheral capsaicin pro-
duces pronociceptive effects, which extends to the development
of hyperalgesia and allodynia (Simone et al., 1989; LaMotte et al.,
1992; Torebjork et al., 1992; Ji et al., 2002). However, capsaicin has
been reported to display antinociceptive properties as well, largely
through TRPV1-dependent mechanisms (Szallasi and Blumberg,
1999; Palazzo et al., 2002; Starowicz et al., 2007; Chiou et al.,
2013). Despite the promise for pain relief, mechanisms respon-
sible for capsaicin’s pro- vs. anti-nociceptive properties remain
poorly understood (Brederson et al., 2013). The current study
seeks to elucidate the neural response to peripherally admin-
istered capsaicin by employing functional magnetic resonance
imaging (fMRI) in awake rats lacking TRPV1 receptors.
With functional imaging the neurobiology of capsaicin-
induced pain in healthy volunteers has extended beyond primary
sensory fibers to include distributed neural circuits (Iadarola
et al., 1998; Baron et al., 1999; Maihofner and Handwerker, 2005;
Zambreanu et al., 2005). The use of 3D segmented, annotated,
brain atlases and computational analysis permits reconstruction
of distributed, integrated neural circuits, or “finger prints” of
brain activity (Ferris et al., 2011). Functional MRI at ultra-high
magnet fields (≥7 Tesla) permits the study of brain activity across
distributed, integrated neural circuits with high temporal and
spatial resolution. Furthermore, the combination of awake fMRI
with an imaging genetics approach (Hariri et al., 2006) represents
a powerful experimental strategy that permits the identification of
neural circuits regulating receptor-specific pain responses. While
imaging genetics in humans takes advantage of natural poly-
morphisms to examine the genetic basis of differences in neural
Frontiers in Systems Neuroscience www.frontiersin.org February 2015 | Volume 9 | Article 15 | 1
SYSTEMS NEUROSCIENCE
2. Yee et al. Pain neural circuits in awake rats
activation, the imaging of transgenic animals represents a more
targeted approach that offers the potential to investigate the con-
tribution of a single gene to neural response patterns. To our
knowledge, these approaches have not yet been applied to the
study of capsaicin-induced pain and pain relief.
To date there are only four published brain imaging stud-
ies on subcutaneous capsaicin-induced pain in rat and all have
been under isoflurane or α-chloralose anesthesia (Malisza and
Docherty, 2001; Malisza et al., 2003; Moylan Governo et al.,
2006; Asanuma et al., 2008). Imaging the neural response to
painful stimuli in awake animals allows identification of multiple,
integrated neural systems involved in sensory discrimination, per-
ception, motivation, and cognition. Borsook and Becerra (2011)
reviewed the many benefits and applications for pain imaging
in awake animals and the limitations introduced by anesthetics
(Borsook and Becerra, 2011).
Here we report a series of neuroimaging experiments on a
newly developed transgenic rat containing a biallelic deletion of
the TRPV1 gene. We demonstrate proof of concept that TRPV1 is
necessary for the production of an integrated neural response to
capsaicin. We show data that inflicting pain in an awake animal
during image acquisition not only activates pain neural circuitry
but also neural circuitry involved in emotion and memory. In
addition, our results suggest an antinociceptive role for capsaicin
that is independent of TRPV1 signaling.
EXPERIMENTAL METHODS
Adult wild-type, male Sprague–Dawley rats (n = 36) weighing
ca 320–350 g were purchased from Charles River Laboratory
(Wilmington, MA). Sprague–Dawley TRPV1 KO rats (n = 12)
were provided by SAGE Laboratories (St. Louis, MO). Rats were
maintained on a 12:12 h light:dark cycle with a lights on at
07:00 h. Animals were allowed access to food and water ad libi-
tum. All rats were acquired and cared for in accordance with
the guidelines published in the Guide for the Care and Use of
Laboratory Animals (National Institutes of Health Publications
No. 85–23, Revised 1985) and adhered to the National Institutes
of Health and the American Association for Laboratory Animal
Science guidelines. The protocols used in this study were in com-
pliance with the regulations of the Institutional Animal Care and
Use Committee at the Northeastern University.
AWAKE ANIMAL IMAGING
Acclimation
A week prior to the first imaging session, all animals were accli-
mated to the imaging system before scanning. Animals were
secured into their holding system while anesthetized with 2–3%
isoflurane. Following cessation of isoflurane, fully conscious rats
were put into a “mock scanner” (a black box with a tape record-
ing of MRI pulses) for 30 min. Acclimation significantly reduces
physiological effects of the autonomic nervous system including
heart rate, respiration, corticosteroid levels, and motor move-
ments (King et al., 2005) helping to improve contrast- to-noise
and image quality.
Drug administration
Capsaicin (1 mg/ml) (Material # M2028 Sigma-Aldrich, St Louis,
MO) was given subdermal in the right hindpaw in a volume of
50 μl via a 27-gauge needle connected to polyethylene (PE) 20
tubing extending from the bore of the magnet to a calibrated
syringe. The same volume in the same hindpaw was given for for-
malin (3%) or 20% Captisol® (a modified β-cyclodextrin) vehicle
(Ligand Pharmaceuticals, Inc. La Jolla, CA). Injections were sepa-
rated by 2 weeks. All injections were performed in the magnet,
under awake conditions during image acquisition. These doses
are sufficient to trigger a pain response, yet small enough to avoid
noticeable tissue damage.
Animal preparation with imaging protocol
Animals were scanned at 300 MHz using quadrature trans-
mit/receive volume coil built into the rat head holder and
restraining system for awake animal imaging (Animal Imaging
Research, Holden, MA). The design of the coil provided com-
plete coverage of the brain from olfactory bulbs to brain stem
with excellent B1 field homogeneity. The design of the restrain-
ing imaging system included a padded head support obviating
the need for ear bars helping to reduce animal discomfort while
minimizing motion artifact. Imaging awake animals removes
the obvious confound of anesthesia on activity of pain neural
circuitry (Borsook and Becerra, 2011).
Image acquisition
Experiments were conducted using a Bruker Biospec 7.0T/20-
cm USR horizontal magnet (Bruker, Billerica, Massachusetts) and
a 20-G/cm magnetic field gradient insert (ID = 12 cm) capa-
ble of a 120-μs rise time (Bruker). At the beginning of each
imaging session, a high-resolution anatomical data set was col-
lected using a single-shot RARE pulse sequence (22 slice; 1.0 mm;
field of vision [FOV] 3.0 cm; 256 × 256; repetition time [TR]
2.5 s; echo time [TE] 12 ms; NEX 2; 2 min acquisition time).
Functional images were acquired using a multi-slice HASTE
pulse sequence (Half Fourier Acquisition Single Shot Turbo
Spin Echo). A single scanning session acquired 22 slices, 1.0 mm
thick, every 6.0 s (FOV 3.0 cm, matrix size 96 × 96, NEX 1)
repeated 150 times for a total time of 15 min. Each scanning
session was continuous, starting with 50 baseline image acqui-
sitions, then hindpaw injection, followed by another 100 image
acquisitions.
Data analysis
Data is co-registered to a mean functional image using
SPM8’s coregistrational code with the following parame-
ters: Quality: 0.97, Smoothing: 0.35 mm, Separation: 0.5 mm.
Gaussian smoothing was performed with a FWHM of 0.8 mm.
Preprocessed functional files were then exported to Medical
Image Visualization and Analysis (MIVA) for registration and
segmentation. Images were aligned and registered to a 3D rat
brain atlas, which is segmented and labeled with 137 discrete
anatomical regions (Kulkarni et al., 2012). The alignment pro-
cess was facilitated by an interactive graphic user interface. The
affine registration process involved translation, rotation and scal-
ing independently and in all three dimensions. Matrices that
transformed each subject’s anatomy were used to embed each slice
within the atlas. All pixel locations of anatomy that were trans-
formed were tagged with regions of interest in the atlas. This
combination created a fully segmented representation of each
Frontiers in Systems Neuroscience www.frontiersin.org February 2015 | Volume 9 | Article 15 | 2
3. Yee et al. Pain neural circuits in awake rats
subject within the atlas. The inverse transformation matrix [Ti]-1
for each subject (i) was also calculated.
In voxel-based analysis, the BOLD % change of each indepen-
dent voxel was averaged for all subjects with a baseline threshold
of 2% BOLD change to account for normal fluctuation of BOLD
signal in the rat brain (Brevard et al., 2003). A composite image
of the whole brain representing the average of all subjects was
constructed for each group for ROI analyses, allowing us to
look at each ROI separately to determine the BOLD change
and the number of activated voxels in each ROI. Further details
on the generation of composite activational maps are provided
in Supplementary Materials. We also compared different points
along the time course of the scan to compare the effects of cap-
saicin over time. For our analyses of the pain pathway, we looked
at activation between 3 and 5 min post-capsaicin. We also com-
pared activation at 2, 5, and 10 min, to compare activation of the
stimulus over time.
The template shown in Figure 1 used to define the neural cir-
cuit of pain in the rat was derived from the work of Gauriau
and Bernard (2002) and meta-analyses from various neuroimag-
ing modalities used to study acute pain in humans (Apkarian
et al., 2005). Using the parabrachial nucleus as a central node,
Gauriau and Bernard described its many efferent connections to
brainstem, hypothalamus, and forebrain areas as comprising the
distributed neural circuit of pain (Gauriau and Bernard, 2002).
They and others (Cechetto et al., 1985; Herbert et al., 1990;
Bernard et al., 1994; Bourgeais et al., 2001b) have provided clear
anatomical and electrophysiological evidence showing two major
pathways of nociceptive fibers emanating from lamina 1 of the
dorsal horn of the spinal cord.
Statistical analysis
Scanning sessions consisted of 150 data acquisitions each, with
a period of 6 s for each image, for a total time lapse of 900 s
or 15 min. Statistical t-tests were performed on each voxel (ca.
15,000 in number) of each subject within their original coordi-
nate system. The average signal intensity in each voxel of the first
5 min of baseline (acquisitions 1–50) was compared to min 0–2
(acquisitions 51–71), min 3–5 (acquisitions 75–105), and min 8–
10 (acquisitions 121–150) following administration of the pain
stimulus or vehicle injection (Figure 2). The baseline threshold
was set at 2%. The t-test statistics used a 95% confidence level,
two-tailed distributions, and heteroscedastic variance assump-
tions. As a result of the multiple t-test analyses performed, a
false-positive detection controlling mechanism was introduced
(Genovese et al., 2002). This subsequent filter guaranteed that,
on average, the false-positive detection rate was below our cutoff
of 0.05.
Volume of activation was compared across experimental
groups using the non-parametric Kruskall–Wallis test statistic.
The brain areas were rank ordered for their significance. Brain
areas were considered statistically different between experimental
groups when comparison produced P-values less than or equal to
our cutoff of 0.05.
Advances over previous imaging studies
There have been numerous studies using various pain-inducing
stimuli to affect changes in brain activity in animals and in
FIGURE 1 | Data analysis. Shown are the statistical comparisons of
different image acquisitions compared to baseline. A non-parametric
Kruskal–Wallis test statistic was used to compare the average signal
intensity in each of ca 15,000 voxel for their first 5 min baseline
(acquisitions 1–50) to min 1–2 (acquisitions 51–71), min 3–5 (acquisitions
75–105), and min 8–10 (acquisitions 121–150) post-capsaicin and formalin.
some cases these have been performed in awake rats as described
here. For example Becerra et al. (Becerra et al., 2011) performed
awake imaging in rats in response to noxious thermal stimuli
and reported activation patterns across numerous brain areas.
However, the present study focuses on capsaicin-induced pain
mediated through the TRPV1 receptor and identifying the dis-
tributed integrated neural circuits engaged through this mech-
anism by using the TRPV1 knockout. The earliest fMRI study
on capsaicin-induced pain in animals used a surface coil and a
gradient-echo pulse sequence to image dorsal forebrain structures
in alpha–chloralose anesthetized rats (Malisza and Docherty,
2001). Performed on a 9.4 T magnet, this study showed clear
event related activation of the anterior cingulate and a less clearly
defined anatomical area referenced as the frontal cortex. The
increased BOLD signal intensity was sustained for about 2–
4 min after subcutaneous injection of capsaicin before returning
to baseline. The BOLD signal change could be blocked by pre-
treatment with morphine. Rats anesthetized with isoflurane and
imaged at 7.0 T with a gradient-echo pulse sequence and sur-
face coil localized to the somatosensory cortex showed a similar
early increase in BOLD signal that could be blocked with mor-
phine (Asanuma et al., 2008). BOLD imaging using a surface
coil at 2.35 T and a spin-echo pulse sequence in isofluorane
anesthetized rats reported activation in the periaqueductal gray,
parabrachial nucleus, pontine reticular nucleus, hippocampus,
and thalamus (Moylan Governo et al., 2006). While this study
included much of the brain it was limited in spatial resolution
to gross brain areas due to the relative insensitivity of fast spin
echo imaging at low field strength. In a recently published paper
Tsurugizawa and colleagues reported changes in brain activity in
awake TRPV1 knockout mice in response to intragastric capsaicin
(Tsurugizawa et al., 2013). Low field strength and a gradient echo
pulse sequence limited the spatial resolution of the signal to gross
areas of the brain, many of which were asymmetric, making any
interpretation of well-defined integrated neural circuits difficult.
The present study, while corroborating these capsaicin-
induced changes in BOLD activation, greatly extended the identi-
fication of the distributed neural circuits by circumventing many
of the problems and limitations in these earlier imaging stud-
ies. First and foremost we imaged awake rats eliminating the
many confounds associated with the use of anesthesia to study
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4. Yee et al. Pain neural circuits in awake rats
FIGURE 2 | Putative pain neural circuit. Shown is a 3D representation of
the different volumes that comprise the putative pain neural circuit. The
central image is a coronal view of a translucent shell of the brain showing the
total composite and location of the different 3D volumes. Surrounding this
are different layers of the neural circuit showing a ventral (deepest) to dorsal
perspective of the different brain volumes. The panels on the top show the
neural circuit in different orthogonal directions. The template used to define
the neural circuit of pain in the rat was derived from the work of Gauriau and
Bernard (2002) and meta-analyses from various neuroimaging modalities
used to study acute pain in humans (Apkarian et al., 2005).
pain-induced changes in brain activity (Borsook and Becerra,
2011). To image the entire brain and improve field homogeneity
we used a quadrature transmit/receive, volume coil. To optimize
space filling and reduce the drop-off of signal due to the distance
between signal source and the receive element, the coil was built
into the head-holder. With an appropriately large rat head, the
fit approximates the distance of a surface coil giving exceptional
signal-to-noise ratio (SNR) and homogeneity over the entire
brain. Lastly we performed BOLD imaging with a spin-echo
pulse sequence instead of the more conventional gradient-echo
sequence in optimize the neuroanatomy and resolution of the
functional scans.
RESULTS
Capsaicin injection into the hindpaw of Sprague–Dawley wild-
type control rats activated many of the areas in the putative
neural circuit of pain, as depicted in Figure 3. Activation maps
depicting the location of the positive BOLD signal change in a
3D rendering of the pain neural circuit (yellow), or in 2D axial
sections from the rat atlas, illustrate the regions activated by cap-
saicin in wild-type rats. The pain neural circuit was adopted from
Gauriau and Bernard using the parabrachial nucleus as key node
(Gauriau and Bernard, 2002). Table 1 lists all of the brain areas
that are significantly activated in wild-type controls following
capsaicin injection as compared to vehicle. This truncated list
is taken from 137 brain areas rank ordered by statistical signifi-
cance (see Supplementary Materials for full Table 1S). Of the 17
brain areas comprising the putative neural circuit for pain, 11
are significantly activated by capsaicin injection as shown high-
lighted in yellow. The gigantocellular reticular nucleus of the pons
trends toward being significant (p < 0.064). The central nucleus
of the amygdala, a key brain area involved in pyschogenic stress
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5. Yee et al. Pain neural circuits in awake rats
FIGURE 3 | Capsaicin-induced pain in wild-type rats. Shown on the
left is a 3D color representation of the different brain areas comprising
the putative pain neural circuit of the rat. The segmented, annotated
illustration is a coronal view. The yellow/gold illustration below is
confluence of the segmented brain areas showing the location of the
average, significant increase (red) in BOLD signal for nine rats, 3–5 min
after capsaicin injection into the right hind-foot. The panel of 2D axial
images on the far left depict the location of significant increase in
BOLD signal (red) in brain slices approximating the positions (A–E)
shown in the 3D illustration.
and fear appears atop the list. The limbic cortex consisting of
the anterior cingulate, retrosplenial, infralimbic, and insular cor-
tices are also represented as is the subiculum, dentate gyrus, and
CA3 of the hippocampus and the paraventricular, mediodorsal
and laterodorsal nuclei of the thalamus. The limbic cortex and
its connections to the dorsal thalamus, hippocampus and amyg-
dala comprise a distributed integrated neural circuit involved in
the processing and memory of emotional experience. Shown in
Figure 4 is a 3D rendering of the cortical loop of Papez and
the activation therein following vehicle injection in wild-type
Sprague–Dawley control rats, capsaicin in TRPV1-KO rats, and
capsaicin in wild-type controls.
Table 2 lists all of the brain areas that are significantly activated
in TRPV1-KO rats following formalin injection. Formalin, which
activates TRPA1 pain receptors, was used as a positive control.
This truncated list is taken from 137 brain areas, rank ordered by
statistical significance (see Supplementary Materials for full Table
2S). There was only modest activation in the vehicle and capsaicin
groups as indicated by the median number of voxels highlighted
in gray. Formalin significantly activated the somatosensory cor-
tex, periaqueductal gray, and medial dorsal thalamus of the pain
neural circuitry shown in yellow. The prelimbic cortex showed a
trend toward significance (P < 0.057). Activation in the cerebel-
lum was also significantly different across experimental groups.
Note the activation of the habenular nucleus. The habenular
nucleus of the thalamus and its connections with basal gan-
glia, e.g., striatum, ventral tegmental area, ventral pallidum, and
accumbens are part of the habenular neural circuit involved with
anticipation and prediction of aversive events. Many areas asso-
ciated with the habenular system were significantly activated or
trended toward significance (blue highlight). The activation of
the habenular system was also observed in capsaicin-injected
wild-type controls as seen in Table 1 highlighted in blue. A 3D
rendering of the habenular system and the activation therein
following vehicle and capsaicin injection is provided in Figure 4.
Second-order post-hoc analysis was performed to examine
pairwise differences between the responses to vehicle and cap-
saicin in TRPV1-KO rats. Table 3 lists all of the brain areas that
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6. Yee et al. Pain neural circuits in awake rats
Table 1 | Volume of activation—positive BOLD in wild-type.
Region of interest Vehicle Capsaicin
Med Max Min Med Max Min P-value
Central amygdala 0 1 0 10 19 3 0.001
Tegmental nucleus 0 1 0 3 9 1 0.001
Temporal ctx 3 9 0 25 46 12 0.001
Parietal ctx 1 2 0 4 8 2 0.001
Entorhinal ctx 15 23 5 99 168 53 0.001
Basal amygdala 0 2 0 6 23 2 0.001
Medial amygdala 0 3 0 9 13 2 0.001
Insular ctx 2 6 0 15 38 3 0.001
Ventral medial hypothalamus 3 8 0 16 21 7 0.001
Auditory ctx 1 6 0 22 36 3 0.001
Lateral amygdala 1 2 0 6 10 1 0.001
Visual ctx 10 30 2 49 96 13 0.001
Somatosensory ctx primary 8 41 0 97 195 19 0.001
Somatosensory ctx secondary 2 13 0 26 66 2 0.002
Motor secondary ctx 30 57 8 78 130 22 0.002
Agranular insular ctx 3 13 0 21 56 2 0.002
Gustatory ctx 1 6 0 17 41 1 0.003
Periaqueductal gray midbrain 10 23 1 28 46 8 0.003
Medial dorsal thalamus 3 11 0 12 15 3 0.003
Bed nucleus stria terminalis 0 11 0 5 25 1 0.004
Habenula thalamus 1 3 0 5 9 0 0.004
Lateral hypothalamus 7 14 0 34 54 7 0.005
Infralimbic ctx 1 6 0 9 19 1 0.005
Ventral lateral striatum 1 18 0 12 34 2 0.005
Parabrachia nucleus 2 6 0 11 15 2 0.005
Dentate gyrus hippocampus 10 16 2 38 59 1 0.005
Paraventricular thalamic nuclei 3 9 0 9 11 3 0.006
Motor ctx primary 17 44 2 37 82 18 0.006
Midbrain reticular nucleus 8 16 1 24 47 6 0.007
Medial preoptic area 3 10 0 11 27 1 0.008
Retrosplenial ctx 13 42 0 40 73 4 0.009
Lateral preoptic area 0 3 0 3 8 0 0.009
Superior vestibular nucleus 3 18 0 20 33 4 0.01
CA3 hippocampus ventral 6 16 0 19 35 2 0.012
Pontine reticular nucleus 5 14 0 19 28 4 0.012
Lateral septal nucleus 11 23 2 25 36 10 0.013
Subiculum hippocampus 13 29 4 50 87 5 0.015
Substantia nigra reticularis 6 11 2 15 20 4 0.016
Dorsal medial striatum 4 9 0 13 19 2 0.017
Dorsal lateral striatum 2 16 0 11 24 2 0.021
Ventral medial striatum 1 14 0 7 15 1 0.023
Anterior cingulate ctx 5 14 0 14 31 2 0.023
Ventral tegmental area 1 7 0 7 12 0 0.055
Gigantocellular reticular n. pons 14 57 4 33 76 9 0.064
Shown is a truncated list of 137 brain areas and their median (med), maximum (max) and minimum (min) number of voxels activated at 3–5 min post-subdermal
injection of vehicle and capsaicin. The brain areas were rank ordered for their statistical significance; the box delineates significant areas. Brain areas were compared
across experimental groups using a non-parametric Kruskall–Wallis test statistic. Brain areas were considered different between experimental groups if P-values
were less than or equal to our cutoff of 0.05. P-values are presented on the far right column. The yellow highlight denotes brain areas comprising the putative neural
network of pain. Areas highlighted in blue comprise the putative neural network of the habenular system.
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7. Yee et al. Pain neural circuits in awake rats
FIGURE 4 | Capsaicin pain in wild-type and TRPV1 rats. Shown are 3D
color representations of the different brain areas comprising the putative pain
neural circuit (top), Papez cortical loop (middle), and the habenular system
(bottom) of the rat. The distinct areas comprising each neural circuit have
been coalesced into a single 3D volume (shown in yellow), and are presented
as a 3 × 3 grid in which rows correspond to each distinct neural circuit and
columns correspond to experimental conditions. In the single 3D volume of
each neural circuit, the red depicts the location of the average significant
increase in BOLD signal 3–5 min after vehicle injection into wild-type
Sprague-Dawley rats (left column), capsaicin injection into TRPV1-KO rats
(middle column), and capsaicin injection into wild-type Sprague–Dawley rats
(right column).
exhibit significant differences in activation. In TRPV1-KO rats,
vehicle treatment resulted in greater activation in 18 brain regions
in comparison to capsaicin treatment. Of these, 4 regions are
part of the putative pain neural circuit. A fifth region that is also
part of the putative pain neural circuit, the gigantocellular retic-
ular nucleus of the pons, displayed a trend toward significance
(P < 0.053).
Figure 5 shows the change in BOLD signal over time in
the anterior cingulate cortex following capsaicin injection in
wild-type controls and formalin injection in TRPV1-KO rats.
The time-courses for both stimuli are very similar, with a
peak in the percent change in BOLD signal occurring 3–4 min
post-injection.
The lateralization of the BOLD signal change following cap-
saicin injection into the right hindpaw was not fixed over the
10 min imaging period post-stimulus as shown in Figure 6. It was
expected that activation would be greatest in the left contralateral
hemisphere of the brain. At 2 min post-injection both positive
and negative BOLD changes appear to be bilateral. At the 5 and
10 min mark, however, the lateralization becomes clearer. This is
also accompanied by an increase in negative BOLD signal in the
right hemisphere.
DISCUSSION
Functional neuroimaging of BOLD responses to painful stimuli
in un-anesthetized, awake animals identified brain regions that
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8. Yee et al. Pain neural circuits in awake rats
Table 2 | Volume of activation—positive BOLD in TRPV1 knockout.
Region of interest Vehicle Capsaicin Formalin
Med Max Min Med Max Min Med Max Min P-value
CA1 hippocampus ventral 0 142 0 0 0 0 7.5 67 1 0.001
Paraventricular thalamic nuclei 0 10 0 0 0 0 4 11 0 0.001
Motor ctx primary 1 245 0 0 5 0 28 133 4 0.002
Medial dorsal thalamus 0 31 0 0 0 0 9 17 0 0.002
Prelimbic ctx 0 67 0 0 0 0 5.5 39 0 0.002
CA3 hippocampus ventral 0 69 0 0 0 0 8 38 0 0.002
CA3 hippocampus dorsal 0 48 0 0 0 0 6.5 26 0 0.002
Anterior thalamic nuclei 0 16 0 0 0 0 7 20 0 0.002
Dentate gyrus hippocampus 0 77 0 0 1 0 9.5 68 0 0.005
Subiculum hippocampus 0 181 0 0 1 0 15 117 0 0.005
Periaqueductal gray midbrain 0 63 0 0 0 0 9 60 0 0.005
Gigantocellular reticular n. pons 0 216 0 0 0 0 6.5 52 0 0.005
Accumbens shell 0 52 0 0 0 0 2 19 0 0.006
Visual ctx 0 189 0 0 9 0 16 239 0 0.008
Somatosensory ctx primary 6 392 0 0 41 0 31 347 3 0.013
Entorhinal ctx 0.5 425 0 0 12 0 31 238 2 0.014
Habenula thalamus 0 9 0 0 2 0 2 9 0 0.019
Piriform ctx 4 191 2 1 20 0 16.5 160 2 0.025
Agranular insular ctx 0.5 102 0 0 20 0 4 69 1 0.028
Anterior cingulate ctx 0 127 0 0 9 0 5.5 56 0 0.034
Principal sensory n. trigeminal 0 61 0 0 0 0 3 32 0 0.05
Shown is a truncated list of 137 brain areas and their median (med, gray highlight), maximum (max) and minimum (min) number of voxels activated at 3–5 min
post-intradermal injection of vehicle, capsaicin and formalin into the hindpaw of TRPV1 knockout rats. The brain areas were rank ordered for their significance; the
tan highlight delineates significant areas. Brain areas were compared across experimental groups using a nonparametric Kruskall–Wallis test statistic. Brain areas
were considered different between experimental groups if P-values were less than or equal to our cutoff of 0.05. P-values are presented on the far right column.
The yellow highlight denotes brain areas comprising the putative neural network of pain.
have previously been shown to mediate neural responses to pain,
corroborating past work with a novel experimental approach.
Furthermore, our data suggest that neuroimaging of pain in
awake, conscious animals has the potential to inform the neuro-
biological basis of full and integrated perceptions of pain which,
as we show here, recruit both affective and learning systems in
addition to areas that subserve pain sensation.
Capsaicin injection in awake wild-type rats activated the
parabrachial nucleus and both major nociceptive pathways, which
include somatosensory areas involved in sensory discrimination
of painful stimuli, and a pathway linking the brainstem with
hypothalamus, midline thalamic areas and limbic cortex involved
in attentional and motivational aspects of pain (see Table 1).
Along with the gigantocellular reticular area, which displayed a
statistical trend of activation in response to capsaicin in wild-
type rats, the parabrachial nucleus has monosynaptic connections
to the periaqueductal gray, ventral medial hypothalamus, central
nucleus of the amygdala, ventral medial and midline thalamic
nuclei (Hylden et al., 1989; Bernard et al., 1993; Bester et al., 1995,
1997; Jasmin et al., 1997; Bourgeais et al., 2001a). The projec-
tion of these areas to the forebrain cortex may function in the
motivational and attentional aspects of pain.
In addition to areas typically thought to comprise the putative
pain neural circuit, we observed capsaicin-induced activation in
limbic and habenular regions. The central nucleus of the amyg-
dala, a key limbic region involved in pyschogenic stress and fear
appears atop the list of capsaicin-activated regions. Areas of the
limbic cortex which included anterior cingulate, retrosplenial,
insular, infralimbic, and orbital cortices, and which comprise
the Papez circuit of emotional experience, were also activated in
response to capsaicin in wild-type control rats. The Papez cir-
cuit connects the hypothalamus and hippocampus to the limbic
cortex through the midline dorsal thalamic nuclei e.g., anterior,
mediodorsal, paraventricular nuclei (Papez, 1937). These areas
send primary projections to the anterior cingulate, retrosplenial,
prefrontal, orbital, and somatosensory cortices. Involvement of
the Papez circuit suggests that conscious processing of TRPV1-
mediated pain responses recruits brain regions that integrate
sensory and attentional information with affective information.
The habenular system was also activated in response to capsaicin
administration in wild-type controls. The habenular system is
associated with anticipation and prediction of aversive events
(Matsumoto and Hikosaka, 2007; Hikosaka et al., 2008). The
influence of the habenular system on aversive learning is medi-
ated, in part, by controlling the activity of dopaminergic neurons
in the midbrain and the subsequent release of dopamine in the
striatum and prefrontal cortex (Matsumoto and Hikosaka, 2007;
Lecourtier et al., 2008). Thus, in addition to corroborating results
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9. Yee et al. Pain neural circuits in awake rats
Table 3 | Volume of activation for positive BOLD in TRPV1 knockout following vehicle and capsaicin.
Region of interest (ROI) Capsaicin Vehicle
Med Max Min Med Max Min P-value
Paraventricular thalamic nuclei 0 2 0 4 11 0 0.001
Outer plexiform layer 2 16 0 0 0 0 0.002
CA3 hippocampus ventral 1 2 0 9 22 0 0.008
Culmen cerebellum 2 4 0 15 68 0 0.009
Nucleus lateral lemniscus 0 2 0 3 11 0 0.009
Anterior lobe pituitary 0 4 0 7 23 0 0.009
Superior vestibular nucleus 0 3 0 3 27 0 0.011
Anterior thalamic nuclei 0 3 0 5 11 0 0.012
Ca1 hippocampus ventral 0 1 0 4 34 0 0.017
Superior colliculus 3 15 0 23 77 1 0.019
Medial pretectal area 0 0 0 0 7 0 0.029
Medial preoptic area 0 1 0 1 11 0 0.032
Medial dorsal thalamus 0 1 0 1 12 0 0.032
Principal sensory nucleus trigeminal 0 5 0 10 29 0 0.033
Periaqueductal gray midbrain 2 6 0 4 37 0 0.035
Ansiform cerebellum 2 4 0 3 76 0 0.037
Simple lobule cerebellum 1 6 0 8 49 0 0.038
Retrosplenial ctx 2 30 0 14 72 0 0.046
Flocculus crebellum 0 3 0 1 7 0 0.052
Gigantocellular reticular nucleus pons 3 9 0 12 93 0 0.053
Shown is a truncated list of 137 brain areas and their median (med, gray highlight), maximum (max) and minimum (min) number of voxels activated at 3–5 min
post-intradermal injection of vehicle and capsaicin into the hindpaw of TRPV1 knockout rats. The brain areas were rank ordered for their significance; the gray line
delineates significant areas. The yellow highlight denotes brain areas comprising the putative neural network of pain.
from past studies, the neuroimaging of pain in awake rats elu-
cidated brain regions that may contribute to the affective and
aversive learning aspects of pain sensing.
Second-order post-hoc analyses revealed unexpected differ-
ences in activation between vehicle and capsaicin treatment
in TRPV1-KO rats. We expected the response to vehicle and
capsaicin administration to be equivalent in rats lacking the
TRPV1 receptor since capsaicin-induced nociception is medi-
ated through binding at the TRPV1 receptor. However, as shown
in Table 3, in rats lacking TRPV1, vehicle administration (in
comparison to capsaicin administration) resulted in greater posi-
tive BOLD response in several brain regions, including those in
the putative pain neural circuit, indicating that capsaicin may
have antinociceptive properties independent of TRPV1 recep-
tor binding. Capsaicin has been previously demonstrated to
have antinociceptive properties under certain conditions (Szallasi
and Blumberg, 1999; Brederson et al., 2013). However, exist-
ing theories of capsaicin-induced antinociception predominantly
rely on the notion that continued binding of capsaicin at the
TRPV1 receptor eventually results in a refractory state whereby
the receptor is desensitized to further capsaicin exposure (Szallasi
and Blumberg, 1999). Capsaicin has been proposed to exhibit
properties independent of TRPV1 binding through direct inhi-
bition of mitochondrial respiration (Athanasiou et al., 2007; Bley
et al., 2012) and this mechanism may also be responsible for the
antinociceptive effects observed in this study. However, future
work should consider the possibility that capsaicin binds to other
receptors that mediate pain relief especially since it has been
shown that anandamide, an endocannabinoid that binds to the
cannabinoid 1 (CB1) receptor to produce analgesic effects, can
also bind to the TRPV1 receptor (Zygmunt et al., 1999; van der
Stelt et al., 2005; Vriens et al., 2009). Future work on TRPV1-
independent antinociceptive effects of capsaicin may be pertinent
to drug development for pain relief.
While capsaicin administration in wild-type rats was capable
of eliciting robust activation in the putative pain neural circuit,
Papez circuit, and the habenular system, rats lacking the TRPV1
receptor displayed minimal activation in these brain regions in
response to capsaicin. As Figure 4 illustrates, capsaicin adminis-
tration to TRPV1-KO rats produced BOLD activation equivalent
to or less than saline vehicle administration to wild-type control
rats. These data demonstrate that expression of the TRPV1 recep-
tor is necessary for the perception of capsaicin-induced pain, and
provide functional verification of the absence of TRPV1 expres-
sion in the transgenic rat model used in this study. Furthermore,
failure to express the TRPV1 receptor throughout the lifespan
did not result in the recruitment of compensatory mechanisms
to facilitate lost capsaicin binding since adult TRPV1-KO rats
did not experience BOLD activation in response to capsaicin
injection. Pain induction through administration of formalin,
mediated through TRPA1 receptor binding, resulted in BOLD
activation in brain regions included in the putative pain neural
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10. Yee et al. Pain neural circuits in awake rats
FIGURE 5 | BOLD signal change over time. Shown is the percent
change in BOLD signal over a 10 min period (acquisitions 51–150)
following capsaicin in wild-type controls (blue) and formalin injection in
TRPV1 KO rats (red). The anterior cingulate cortex, a key area in the
pain neural circuit, shows a maximal change in BOLD signal within
3–5 min post-injection of capsaicin or formalin. Trend lines (solid blue
and red) represent simple moving averages over 25 timepoints. Vertical
lines denote SEM.
FIGURE 6 | Lateralization of BOLD signal change over time. Shown
below are activation maps of positive and negative BOLD signal
following capsaicin injection into the right hindpaw of wild-type
Sprague–Dawley rats (n = 9). The contralateral (left side) somatosensory
cortex is circled in yellow for each time point. There is no clear
lateralization of positive BOLD in the first 2 min of data acquisition.
Instead there appears to be more negative BOLD as compared to the
ipsilateral somatosensory cortex (right side). However, by 5 and 10 min
post-capsaicin the contralateral side presents with more positive BOLD
signal. Areas of activation have been smoothed. Colored BOLD
activation scales indicate percent changes in positive BOLD (red
spectrum) and negative BOLD (blue spectrum).
circuit, demonstrating the ability of this transgenic model to
cause specific disruption of TRPV1-mediated pain. Examination
of the time course of BOLD activation provides a depiction
of how the processing of painful stimuli unfolds in the brain.
Figure 5 illustrates the change in BOLD signal in the anterior
cingulate cortex over the course of the 10 min imaging session
following administration of capsaicin in wild-type rats and for-
malin in TRPV1-KO rats. Maximal change in BOLD signal peaks
3–5 min following the injection of both capsaicin in wild-type rats
and formalin in TRPV1-KO rats, illustrating the similarity in the
temporal dynamics of the BOLD activation. Taken together these
data validate the usage of the TRPV1-KO rat for the experimental
study of pain.
Lateralization of BOLD signal across the imaging session was
not fixed, and was not yet present 2 min following injection of
capsaicin. Indeed, dynamic fluctuations in negative and posi-
tive BOLD signal occur across the cerebral hemispheres within
the first 1–2 min of stimulation (as shown in Figure 6). These
fluctuations in BOLD signal appeared to stabilize between 3
and 5 min. Interestingly, rapid fluctuation of BOLD signal across
hemispheres in response to a noxious forepaw stimulus in anes-
thetized rats has been reported previously (Tuor et al., 2000).
However, 5 min following capsaicin administration, wild-type
rats displayed lateralization of BOLD signal changes with greater
activation in the contralateral hemisphere, as expected. Imaging
neural responses to painful stimuli in awake, conscious animals
revealed a lateralized pattern of activational changes that unfolded
over the timecourse of the imaging session.
CAVEATS AND DATA INTERPRETATION
For any imaging study on awake animals the issues and conse-
quences related to the stress of head restraint and restricted body
movement must be considered. Protocols have been developed to
help lessen the stress of an imaging study by acclimating animals
to the environment of the MR scanner and the restraining devices.
Such procedures have been shown in past studies to reduce stress
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