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Optogenetic dissection of medial prefrontal cortex circuitry.

Riga D, Matos MR, Glas A, Smit AB, Spijker S, Van den Oever MC - Front Syst Neurosci (2014)

Bottom Line: 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.This provides important novel insights in the contribution of specific neuronal subpopulations and their connectivity to mPFC function in health and disease states.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije University Amsterdam Amsterdam, Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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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.

Mentions: The first optogenetic experiments that directly assessed the role of mPFC activity in depression-like behavior confirmed that activation of vmPFC neurons reverses depressive-like symptomatology in a depression-vulnerable population of mice (Covington et al., 2010; Figure 1). In this study, the authors used the chronic social defeat paradigm, a depression model with high face, predictive and construct validity (Nestler and Hyman, 2010) to distinguish mice on their resilience/vulnerability to social stress. Photostimulation of the vmPFC was achieved using a herpes simplex virus (HSV) viral vector coding for ChR2 driven by the IE4/5 promoter, which targeted ChR2 to mPFC neurons in a non-selective manner (Covington et al., 2010). Specifically, the ILC and PLC of stress-susceptible mice were stimulated in a pattern similar to DBS parameters that previously alleviated depressive symptoms, mimicking cortical burst firing (Hamani et al., 2010a). Photostimulation fully restored social interaction scores and diminished anhedonia, as expressed in preference for drinking a sucrose solution over water, without altering anxiety levels or social memory performance (Covington et al., 2010). Notably, traditional mPFC manipulations have led to contradictory observations. For example, generic mPFC lesions led to the expression of depressive-like behavior, including learned helplessness (Klein et al., 2010), whereas transient pharmacological inactivation of the ILC resulted in an antidepressant response, as assessed by the FST (Slattery et al., 2011). These opposing findings might originate from the different temporal resolution of the methodologies and/or the different (sub) regions examined, e.g., whole mPFC (Klein et al., 2010) vs. vmPFC (Covington et al., 2010) or ILC (Slattery et al., 2011). As optogenetic activation of the vmPFC by Covington et al. (2010) was not specific for a particular neuronal subtype, the direction of the net effect of stimulation at the circuit level remains unresolved. These data may reflect the variability of mPFC involvement seen in human studies, which support either reduced or increased activity of distinct frontal areas in the expression of the depressive state.


Optogenetic dissection of medial prefrontal cortex circuitry.

Riga D, Matos MR, Glas A, Smit AB, Spijker S, Van den Oever MC - Front Syst Neurosci (2014)

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.
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Related In: Results  -  Collection

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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.
Mentions: The first optogenetic experiments that directly assessed the role of mPFC activity in depression-like behavior confirmed that activation of vmPFC neurons reverses depressive-like symptomatology in a depression-vulnerable population of mice (Covington et al., 2010; Figure 1). In this study, the authors used the chronic social defeat paradigm, a depression model with high face, predictive and construct validity (Nestler and Hyman, 2010) to distinguish mice on their resilience/vulnerability to social stress. Photostimulation of the vmPFC was achieved using a herpes simplex virus (HSV) viral vector coding for ChR2 driven by the IE4/5 promoter, which targeted ChR2 to mPFC neurons in a non-selective manner (Covington et al., 2010). Specifically, the ILC and PLC of stress-susceptible mice were stimulated in a pattern similar to DBS parameters that previously alleviated depressive symptoms, mimicking cortical burst firing (Hamani et al., 2010a). Photostimulation fully restored social interaction scores and diminished anhedonia, as expressed in preference for drinking a sucrose solution over water, without altering anxiety levels or social memory performance (Covington et al., 2010). Notably, traditional mPFC manipulations have led to contradictory observations. For example, generic mPFC lesions led to the expression of depressive-like behavior, including learned helplessness (Klein et al., 2010), whereas transient pharmacological inactivation of the ILC resulted in an antidepressant response, as assessed by the FST (Slattery et al., 2011). These opposing findings might originate from the different temporal resolution of the methodologies and/or the different (sub) regions examined, e.g., whole mPFC (Klein et al., 2010) vs. vmPFC (Covington et al., 2010) or ILC (Slattery et al., 2011). As optogenetic activation of the vmPFC by Covington et al. (2010) was not specific for a particular neuronal subtype, the direction of the net effect of stimulation at the circuit level remains unresolved. These data may reflect the variability of mPFC involvement seen in human studies, which support either reduced or increased activity of distinct frontal areas in the expression of the depressive state.

Bottom Line: 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.This provides important novel insights in the contribution of specific neuronal subpopulations and their connectivity to mPFC function in health and disease states.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije University Amsterdam Amsterdam, Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus