Optogenetic dissection of medial prefrontal cortex circuitry

Abstract

The medial prefrontal cortex (mPFC) is critically involved in numerous cognitive functions, including attention, inhibitory control, habit formation, working memory and long-term memory. Moreover, through its dense interconnectivity with subcortical regions (e.g., thalamus, striatum, amygdala and hippocampus), the mPFC is thought to exert top-down executive control over the processing of aversive and appetitive stimuli. Because the mPFC has been implicated in the processing of a wide range of cognitive and emotional stimuli, it is thought to function as a central hub in the brain circuitry mediating symptoms of psychiatric disorders. New optogenetics technology enables anatomical and functional dissection of mPFC circuitry with unprecedented spatial and temporal resolution. This provides important novel insights in the contribution of specific neuronal subpopulations and their connectivity to mPFC function in health and disease states. In this review, we present the current knowledge obtained with optogenetic methods concerning mPFC function and dysfunction and integrate this with findings from traditional intervention approaches used to investigate the mPFC circuitry in animal models of cognitive processing and psychiatric disorders.

Keywords: addiction; cognition; depression; fear; memory; optogenetics; prefrontal cortex.

Figure 1

Optogenetic evidence for the involvement of the mPFC in depressive-like behavior and anxiety. Yellow flash: photoinhibition; blue flash: photoactivation; ↑ = pro-depressive/anxiogenic effects; ↓ = antidepressant/anxiolytic effects. ¹Covington et al. (2010): photoactivation increased sucrose preference and restored social interaction in defeat-susceptible mice. ²Kumar et al. (2013): photoactivation layer V pyramidal cells decreased immobility FST in naïve animals. ³Kumar et al. (2013): photoactivation layer V pyramidal cells increased time in open arms EPM test in defeated animals. ⁴Warden et al. (2012): photoactivation of mPFC-LHb projection promoted immobility FST in naïve animals. ⁵Warden et al. (2012): photoactivation of mPFC-DRN projection decreased immobility FST in naïve animals. ⁶Challis et al. (2014): photoactivation of vmPFC-DRN projection reduced social interaction in naïve animals. ⁷Challis et al. (2014): photoinhibition of vmPFC-DRN projection prevented social withdrawal in defeated animals. ⁸Vialou et al. (2014): photoactivation of dmPFC-Nac projection prevented social withdrawal. ⁹Vialou et al. (2014): photoactivation of dmPFC-BLA projection increased time in open arms EPM test. ¹⁰Chaudhury et al. (2013): photoinhibition of VTA-mPFC DA projection reduced social interaction in sub-threshold defeat animals. ¹¹Friedman et al. (2014): photoactivation of VTA-mPFC DA projection restored social interaction in defeat-susceptible mice. ¹²Gunaydin et al. (2014): photoactivation of VTA-mPFC DA projection evoked anxiety-like behavior and place avoidance in naïve mice. dmPFC: dorsal medial prefrontal cortex; vmPFC: ventral medial prefrontal cortex; NAcc: nucleus accumbens core; NAcsh: nucleus accumbens shell; LHb: lateral habenula; DRN: dorsal raphe nucleus; BLA: basolateral amygdala; VTA: ventral tegmental area.

Figure 2

Optogenetic evidence for the involvement of the mPFC in addictive behavior. Yellow flash: photoinhibition; blue flash: photoactivation. ↑ = enhanced drug taking/seeking; ↓ = reduced drug taking/seeking. Optogenetic manipulations indicate that the circuitry that regulates drug taking (when the drug is available) differs from the circuitry that mediates drug seeking (in absence of the drug). (A) Manipulation of drug taking. ¹Chen et al. (2013): photoactivation PLC diminished compulsive cocaine taking in aversion resistant rats. ²Chen et al. (2013) and Martín-García et al. (2014): photoinhibition PLC evoked compulsive cocaine taking in aversion sensitive rats and resumption of cocaine intake in rats with history of high-frequency self-administration. ³Seif et al. (2013): photoinhibition of dmPFC-NAcc projection reduced alcohol intake paired with aversive stimulus. (B) Manipulation of drug seeking. ⁴Stefanik et al. (2013) and Martín-García et al. (2014): photoinhibition dmPFC attenuated cocaine seeking. ⁵Stefanik and Kalivas (2013): photoinhibition of BLA-dmPFC projection reduced reinstatement of cocaine seeking. ⁶Van den Oever et al. (2013): photoactivation vmPFC facilitated extinction of remote, but not recent, cocaine memory. ⁷Van den Oever et al. (2013): photoinhibition vmPFC impaired recall of recent cocaine memory, but prevented extinction of remote cocaine memory. ⁸Ma et al. (2014): photoactivation (1 Hz) evoked LTD in vmPFC-NAcsh projection reversed cocaine-induced synaptic adaptation and enhanced subsequent cocaine seeking. ⁹Pascoli et al. (2012): photoactivation (1 Hz) of vmPFC-NAcsh projection reversed cocaine-induced synaptic adaptation and locomotor sensitization. ¹⁰Pascoli et al. (2014): photoactivation (13 Hz) of vmPFC-NAcsh projection reversed cocaine-induced synaptic adaptation and abolished cocaine seeking. ¹¹Ma et al. (2014): photoactivation (1 Hz) evoked LTD in dmPFC-NAcc projection reversed cocaine-induced synaptic adaptation and decreased subsequent cocaine seeking. ¹²Stefanik et al. (2013): photoinhibition of PLC-NAc core projection attenuated cocaine-primed reinstatement of cocaine seeking.