125 S 31st street
|08/28/2013: Collin Challis' new paper is Out in J Neuroscience|
Collin Challis,a grad Student in the Penn Neuroscience Graduate Group reports on experiments he has been conducting during the past 2 years in collaboration with Sheryl Beck at CHOP examining the microcircuit underlying the top-down control of serotonin circuits in the brainstem Raphe. |
Collin finds that these circuits are affected functionnally and morphologically by adverse social experiences and and he shows that these neuroplastic changes directly contribute to the expression of social avoidance.
Serotonin has a prominent role in social interaction both in human and animals: low serotonin levels are associated with social avoidance and aggression, whereas elevated levels promote affiliative behaviors and dominance. Serotonin levels in the brain are determined primarily by the activity of serotonergic neurons in the median and dorsal raphe nuclei (DRN). These neurons are inhibited by local GABAergic neurons, which therefore also regulate social interactions.
Collin finds that the activity of GABAergic neurons become sensitized in mice that avoid interaction with other mice (that is, exhibit social defeat, SD) after being repeatedly caged with an aggressor, but does not increase in resilient mice and this coincides with nearby serotonin neurons receiving more GABAergic inhibition.
Remarkably, silencing GABAergic neurons and thereby lifting the brake from DRN serotonin neurons during a critical period of SD training prevented the development of social avoidance without affecting the development of anxiety-like behaviors in defeated mice.
Collin's results are important as they point out to new mechanisms that could be relevant to negative sociocognitive biases, and important symptomatic dimension of affective disorders.
||Social AVoidance , Top down control ,Brainstem raphe, interneurons , GABA,
|08/19/2013 Jeanine Jochems' new paper is Out in Neuropsychopharmacology|
Jeanine Jochems, a grad Student in the Penn Pharmacology Graduate Group reports on her studies examining the behavioral effects the first HDAC6 selective inhibitors that effectively cross the blood brain barrier. Studies were conducted in collaboration with Acetylon Pharmaceuticals Inc.,a company leader in targeted epigenetic drug discovery Inc http://www.acetylon.com. |
In her paper now online @ Neuropsychopharmacology Jeanine establishes that the 2 novel HDAC6-selective inhibitors (ACY738 and ACY-775) increase acetylation of non-histone proteins in the mouse brain and produce rapid behavioral effects that are superior to those of classical antidepressants in several animal models of depression, including the social defeat paradigm.http://www.nature.com/npp/journal/vaop/naam/abs/npp2013207a.html,
Jeanine also validates the central mode of action of these compounds by showing that the probes are behaviorally inactive when they are administered to genetically altered mice that lack HDAC6 selectively in CNS neurons.
Interestingly, when they are co-administered with low doses of SSRIs, these new HDAC6 inhibitors dramatically potentiate the behavioral activity of the antidepressants, suggesting a crosstalk between the mechanisms of action of these two classes of drugs.
In contrast to the class I HDACs (HDAC1/HDAC2/HDAC3)that are expressed ubiquitously throughout the CNS, we find that HDAC6 is expressed regionally and appear enriched in certain cell types, like serotonin neurons (see top panel below). Thus the signaling crosstalk may occur more predominantly in these subtypes of neurons. The exact signaling mechanisms mediating the rapid behavioral activity of HDAC6 inhibitors remain unclear at the monment. But this mechanism may likely involve the hyperacetylation of cytoskeletal proteins like Tubulin and Cortactin that regulate the stability of denditic trees and spines or chaperones proteins like Hsp90 that are important modulators of steroid hormone signaling.
Because new HDAC6 inhibitors are devoid of activity on Class I HDACs (i.e. the ones that regulate chromatin) they have a drastically improved toxicity profile over broad acting first generation HDAC inhibitors like SAHA and TSA. This makes them more plausible candidates for potential clinical studies in neuropsychiatric disorders.
In 2012 we filed a patent conjointly with Acetylon Pharmaceuticals in the perspective of developing some of these HDAC6 selective inhibitors as potential novel treatments for stress-related behavioral disorders.
||HDACs, HDAC6, depression models , antidepressants
|7/12/2012 Collin strikes again !|
Collin Challis strikes again, this time winning the Award of the best basic science poster a the Annual meeting of the Society of Biological Psychiatry , which this year took place right here in Philly, |
- Let's hope Collin's NRSA reviewers will share the enthusiasm of SOBP's poster committee...
|6/7/2012 Collin Challis wins IBNS travel Award|
Congrats to Collin Challis who received one of the 10 Grad student travel awards that the IBNS attributes every year for talented students to come present their exciting work at the International Behavioral Neuroscience Meeting. |
This year the meeting was taking place at the Sheraton Keauhou Bay, Kailua-Kona, Hawaii-
Here is a picture of Collin during his heroic presentation !
Graduate Student Travel Awards
|PROJECT#1 ROLE OF HDAC6 IN A MURINE MODEL OF AFFECTIVE DISORDER AND ANTIDEPRESSANT ACTION 1R01MH087581-01A1|
DESCRIPTION (provided by applicant): |
The HDAC6 gene that we propose to study in this project is a novel therapeutic candidate emerged from the burgeoning field of epigenetics. Histone deacetylases (HDACs) are the therapeutic targets of a novel class of anticancer therapies called HDAC inhibitors. Non-selective inhibitors of histone deacetylases, which promote protein hyperacetylation in the brain, have demonstrated consistent behavioral activity across various rodent models, including models of affective disorders and antidepressant response. Although most studies, so far, have interpreted this antidepressant-like activity in the context of chromatin-remodeling mechanisms (ie the canonical role of HDACs) it is now well established that the influence of protein acetylation on cellular processes extends far beyond transcriptional regulation. In fact, certain deacetylases, of which HDAC6 is a prominent example, are involved primarily in "non-histone" functions. These functions comprise, for instance, the regulation of HSP90's chaperone activity, an important component of steroid receptors signaling. Through this mechanism, HDAC inhibitors have recently been shown to blunt Glucocorticoid Receptor (GR) function, one of the main receptors for stress steroid hormones. Our preliminary data indicate that HDAC6 is enriched in the serotonin system, the primary target of most antidepressants currently used in the clinic. Here, we propose to test the hypothesis that inhibition of HDAC6 constitutes a candidate therapeutic mechanism for antidepressant and pro-resilience interventions through focused inhibition of GR signaling within the serotonergic system. To test this hypothesis we propose the following aims. Our Aim I is to conduct a comprehensive regional and cellular mapping of HDAC6 mRNA and protein in the mouse brain, and to start evaluating the pattern of HDAC6 expression in the human brain. Our Aim II is to evaluate the behavioral consequences of HDAC6 manipulations in 5-HT system. Here we will combine pharmacological approaches with serotonin-specific gain and loss of function of HDAC6 in the live animal. Consequences of these manipulations will be examined in a battery of tests measuring resilience to chronic stress as well as sensitivity to acute and chronic effects of antidepressants. Our Aim III is to examine HDAC6's influence on GR signaling in 5-HT neurons. Here, we will use a combination of in vivo and cell culture-based assays to characterize the effect of HDAC6 KO and HDAC6 pharmacological inhibition on HSP90 acetylation, GR translocation and GR-mediated gene regulation. The goals of this project connect in 2 major ways with areas of high priority defined by the NIH in the field of Neuroscience and Basic Behavioral Science. First, this proposal will increase our understanding of the fundamental mechanisms of complex social behavior relevant to the socio-affective component of depressive symptomatology. Second, we hope to validate HDAC6 as a new molecular target relevant to the treatment of mental disorders.
Public Health Relevance Statement:
Project Narrative This project is integral to our long term endeavor to elucidate the molecular and cellular mechanisms underlying antidepressants therapeutic activity. A greater understanding of these mechanisms is a critical prerequisite to the discovery of new antidepressant therapies, with faster onset and enhanced efficacy, which are greatly needed in Psychiatric clinics. In the present project we propose to evaluate, using animal models, the potential of histone deacetylase 6 (HDAC6) as a new therapeutic target for antidepressant treatments.
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