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
• http://www.youtube.com/watch?v=I64X7vHS
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).
– 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).
• 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)
– 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).
Resilience to Chronic Stress Is Mediated by Hippocampal BrainDerived 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 & postacute 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 antidepressantlike 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
Thank You