Antidepressant effect of optogenetic stimulation of the mPFC Herbert E. Covington III, Mary Kay Lobo, Ian Maze, Vincent Vialou, James M. Hyman, Samir Zaman, Quincey LaPlant, Ezekiel Mouzon, Subroto Ghose, Carol A. Tamminga, Rachael L. Neve, Karl Deisseroth & Eric J. Nestler., J of Neuroscience Presented by: Justin P. Smith

Intro Optogenetics HOE HOE

Franklin & Mansuy review Behavioral models Environmental manipulations for Adults Neuroendocrine System BDNF

Maternal Behavioral Models

BDNF Signaling component of stress In hippocampus, necessary and sufficient for resilience. – BDNF mRNA increased in CA3 in rats resilient to chronic mild stress (Bergström et al., 2008).Bergström et al., 2008 – Overexpressed in the adult DG, promotes resilience and blocks the anhedonic effect of stress Knockdown in young animals ↑ corticosterone level & induces depressive-like behaviors and anhedonia (Taliaz et al., 2010, 2011).Taliaz et al., BDNF expression increases when glutamate release is higher, suggesting a dual interaction between BDNF and glutamatergic transmission In PVN, BDNF acts through TrkB-CREB signaling, induces CRH expression (Jeanneteau et al., 2012)Jeanneteau et al., 2012 – Suggests distinct downstream pathways in different brain areas Sustained ↑ in excitatory synaptic transmission and ↓ level of trophic factors in hippocampus following stress may underlie the dendritic remodeling and volumetric shrinkage associated with stress-related pathologies in animals and humans (Maras and Baram, 2012).Maras and Baram, 2012

Resilience to Chronic Stress Is Mediated by Hippocampal Brain- Derived Neurotrophic Factor Rats subjected to 4 weeks of chronic mild stress (CMS) -- depressive-like behaviors Lentiviral vectors used induce localized BDNF overexpression (OE) or knockdown (KD) in hippocampus Behavioral outcome measured 3 weeks after the CMS – plasma for corticosterone levels – Hippocampal tissue for BDNF measurements Hippocampal BDNF expression plays a critical role in resilience to chronic stress – ↓ of hippocampal BDNF expression in young (but not adult) induces prolonged ↑ corticosterone secretion Describes mech for individual differences in responses to chronic stress and implicates hippocampal BDNF in the development of neural circuits that control adequate stress adaptations

Fig 3: Behavioral effects of CMS & hipp BDNF expression in adult rats BDNF OE in dDG blocks depressive –like effects of CMS

Fig 4: Behavioral effects of CMS & hipp BDNF expression in young rats Something clever about young rat results

Fig 5: Cort plasma lvls- young & adult, baseline & post- acute stress Young Rats Adult Rats

Antidepressant Effect of Optogenetic Stimulation of the Medial Prefrontal Cortex Remember that video? Role of PFC in antidepressant response IEG’s involved (to show activity) Hypothesis – mPFC stimulation may generate antidepressant- like behavioral responses in SUSCEPTIBLE mice subjected to chronic social defeat stress

Materials and Methods 2 days before exp singly housed- seems short Behavioral tests – Social interaction – Sucrose preference – Social recognition – EPM

Exp1: IEG expression in depressed human postmortem prefrontal cortical tissue Controls vs. Depressed Anterior cingulate cortex (Broadmann area 24)

Fig 1: ↓ IEG expression in depressed humans

Exp 2: IEG expression in the mPFC of mice after chronic social defeat stress Chronic social defeat – B6 vs novel CD1 5 min/10days 8 mice from each group (susceptible, resilient, control) selected for IEG analysis

Fig 2: Deficits in IEG expression in mPFC post chronic social defeat stress

Exp 3: antidepressant effects of optogenetic stimulation of the mPFC Assessed whether or not optogenetic stim of mPFC reverses social avoidance induced by chronic social defeat stress OPTOGENETICS!

Fig 3: Optogenetic stim of mouse mPFC reverses depression-like symptoms induced by chronic social defeat stress

Fig 4: Optogenetic stimulation of the mPFC increases immediate early gene expression

Discussion IEG downregulated in humans (ACC) and stressed mice (mPFC) suggests impaired cortical activity, ↓ burst firing patterns in mPFC may contribute to emotional disturbances Optogenetically mimicking burst-like activity produced anti-depressant-like behavior

IEG comments Optogenetic stim ↑ ERG1 (zif268) – Not arc – Both associated with conditioned behaviors arc, context dependent? – Needs numerous cellular events extracellular signal-regulated kinase, – PKA & PKC Resilient mice, ↑ arc expression Restoring functional activity levels necessary requirement of antidepressant action

Coving optogenetic bases Virus, neuron specific – Hits excitatory pyramidal AND GABAergic interneurons Unable to determine if ↑ OR ↓ mPFC circuit Hypothesis: optogenetic stimulation of mPFC used here increases the firing of descending projection neurons that target other limbic brain regions as well as subcortical monoaminergic nuclei

Take Home Brain stim within mPFC effective for treating depression

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