Comorbid anxiety-like behavior in a rat model of colitis is mediated by an upregulation of corticolimbic fatty acid amide hydrolase

Peripheral inflammatory conditions, including those localized to the gastrointestinal tract, are highly comorbid with psychiatric disorders such as anxiety and depression. These behavioral symptoms are poorly managed by conventional treatments for inflammatory diseases and contribute to quality of life impairments. Peripheral inflammation is associated with sustained elevations in circulating glucocorticoid hormones, which can modulate central processes, including those involved in the regulation of emotional behavior. The endocannabinoid (eCB) system is exquisitely sensitive to these hormonal changes and is a significant regulator of emotional behavior. The impact of peripheral inflammation on central eCB function, and whether this is related to the development of these behavioral comorbidities remains to be determined. To examine this, we employed the trinitrobenzene sulfonic acid-induced model of colonic inflammation (colitis) in adult, male, Sprague Dawley rats to produce sustained peripheral inflammation. Colitis produced increases in behavioral measures of anxiety and elevations in circulating corticosterone. These alterations were accompanied by elevated hydrolytic activity of the enzyme fatty acid amide hydrolase (FAAH), which hydrolyzes the eCB anandamide (AEA), throughout multiple corticolimbic brain regions. This elevation of FAAH activity was associated with broad reductions in the content of AEA, whose decline was driven by central corticotropin releasing factor type 1 receptor signaling. Colitis-induced anxiety was reversed following acute central inhibition of FAAH, suggesting that the reductions in AEA produced by colitis contributed to the generation of anxiety. These data provide a novel perspective for the pharmacological management of psychiatric comorbidities of chronic inflammatory conditions through modulation of eCB signaling

A roadmap for research in post-stroke fatigue:Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable

Rationale: Fatigue affects almost half of all people living with stroke. Stroke survivors rank understanding fatigue and how to reduce it as one of the highest research priorities. Methods: We convened an interdisciplinary, international group of clinical and pre-clinical researchers and lived experience experts. We identified four priority areas: (1) best measurement tools for research, (2) clinical identification of fatigue and potentially modifiable causes, (3) promising interventions and recommendations for future trials, and (4) possible biological mechanisms of fatigue. Cross-cutting themes were aphasia and the voice of people with lived experience. Working parties were formed and structured consensus building processes were followed. Results: We present 20 recommendations covering outcome measures for research, development, and testing of new interventions and priority areas for future research on the biology of post-stroke fatigue. We developed and recommend the use of the Stroke Fatigue Clinical Assessment Tool. Conclusions: By synthesizing current knowledge in post-stroke fatigue across clinical and pre-clinical fields, our work provides a roadmap for future research into post-stroke fatigue

A roadmap for research in post-stroke fatigue: consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable

Rationale: Fatigue affects almost half of all people living with stroke. Stroke survivors rank understanding fatigue and how to reduce it as one of the highest research priorities. Methods: We convened an interdisciplinary, international group of clinical and pre-clinical researchers and lived experience experts. We identified four priority areas: (1) best measurement tools for research, (2) clinical identification of fatigue and potentially modifiable causes, (3) promising interventions and recommendations for future trials, and (4) possible biological mechanisms of fatigue. Cross-cutting themes were aphasia and the voice of people with lived experience. Working parties were formed and structured consensus building processes were followed. Results: We present 20 recommendations covering outcome measures for research, development, and testing of new interventions and priority areas for future research on the biology of post-stroke fatigue. We developed and recommend the use of the Stroke Fatigue Clinical Assessment Tool. Conclusions: By synthesizing current knowledge in post-stroke fatigue across clinical and pre-clinical fields, our work provides a roadmap for future research into post-stroke fatigue

Development of the febrile response to pyrogens in the foetal and newborn lamb

Bibliography: p. 150-183

Unexpected Microglial “De-activation” Associated With Altered Synaptic Transmission in the Early Stages of an Animal Model of Multiple Sclerosis

Multiple sclerosis, and its animal model—experimental autoimmune encephalomyelitis (EAE), is a demyelinating disease causing motor and sensory dysfunction, as well as behavioral comorbidities. In exploring possible functional changes underlying behavioral comorbidities in EAE, we observed increased excitatory drive onto the major cells of the basolateral amygdala. This was associated with increased numbers of dendritic spines. An unexpected finding was that microglial cells at this time were in a “deactivated” state, and further studies suggested that the microglial deactivation was responsible for the increased excitatory drive. This is the first report of microglial deactivation in an inflammatory disease and raises many questions as to the underlying mechanisms and functional relevance

Metaplasticity of Hypothalamic Synapses following In Vivo Challenge

SummaryNeural networks that regulate an organism's internal environment must sense perturbations, respond appropriately, and then reset. These adaptations should be reflected as changes in the efficacy of the synapses that drive the final output of these homeostatic networks. Here we show that hemorrhage, an in vivo challenge to fluid homeostasis, induces LTD at glutamate synapses onto hypothalamic magnocellular neurosecretory cells (MNCs). LTD requires the activation of postsynaptic α2-adrenoceptors and the production of endocannabinoids that act in a retrograde fashion to inhibit glutamate release. In addition, both hemorrhage and noradrenaline downregulate presynaptic group III mGluRs. This loss of mGluR function allows high-frequency activity to potentiate these synapses from their depressed state. These findings demonstrate that noradrenaline controls a form of metaplasticity that may underlie the resetting of homeostatic networks following a successful response to an acute physiological challenge