Bidirectional Optogenetically-Induced Plasticity of Evoked Responses in the Rat Medial Prefrontal Cortex Can Impair or Enhance Cognitive Set-Shifting.

Chronic stress compromises cognition, including executive function mediated in the medial prefrontal cortex (mPFC). To investigate mechanisms underlying these processes, we use chronic unpredictable stress (CUS), which reduces activity in the mPFC and impairs cognitive set-shifting, a measure of cognitive flexibility in laboratory rats. It has been shown that CUS attenuates the local electrical field potential response evoked in the mPFC by stimulation of the ascending excitatory afferent from the mediodorsal thalamus (MDT). Thus, in this study, to investigate the role that such changes in afferent-evoked responsivity of the mPFC might play in the cognitive deficits induced by CUS, we used optogenetics to directly induce plastic changes in the thalamic-mPFC afferent pathway. Glutamatergic neurons in the MDT were virally-induced to express the ChETA variant of channelrhodopsin. Then, to first validate the optogenetic induction of plasticity, long-term depression (LTD) or long-term potentiation (LTP) were induced by laser stimulation of ChETA-expressing terminals in the mPFC of anesthetized rats. In subsequent experiments, induction of opto-LTD in awake animals produced set-shifting deficits similar to those induced by CUS. By contrast, inducing opto-LTP in rats that had received prior CUS treatment corrected the stress-induced deficit in set-shifting. These results suggest that stress-induced plasticity in the thalamic-mPFC pathway is sufficient to produce stress-induced cognitive deficits, and may represent a novel target for effective therapeutic intervention to correct cognitive impairment in stress-related psychiatric disorders.

Ciliary neurotrophic factor signaling in the rat orbitofrontal cortex ameliorates stress-induced deficits in reversal learning.

Deficits in cognitive flexibility, i.e. the ability to modify behavior in response to changes in the environment, are present in several psychiatric disorders and are often refractory to treatment. However, improving treatment response has been hindered by a lack of understanding of the neurobiology of cognitive flexibility. Using a rat model of chronic stress (chronic intermittent cold stress, CIC) that produces selective deficits in reversal learning, a form of cognitive flexibility dependent on orbitofrontal cortex (OFC) function, we have previously shown that JAK2 signaling is required for optimal reversal learning. In this study we explore the molecular basis of those effects. We show that, within the OFC, CIC stress reduces the levels of phosphorylated JAK2 and of ciliary neurotrophic factor (CNTF), a promoter of neuronal survival and an activator of JAK2 signaling, and that neutralizing endogenous CNTF with an intra-OFC microinjection of a specific antibody is sufficient to produce reversal-learning deficits similar to stress. Intra-OFC delivery of recombinant CNTF to CIC-stressed rats, at a dose that induces JAK2 and Akt but not STAT3 or ERK, ameliorates reversal-learning deficits, and Akt blockade prevents the positive effects of CNTF. Further analysis revealed that CNTF may exert its beneficial effects by inhibiting GSK3ß, a substrate of Akt and a regulator of protein degradation. We also revealed a novel mechanism of CNTF action through modulation of p38/Mnk1/eIF4E signaling. This cascade controls translation of select mRNAs, including those encoding several plasticity-related proteins. Thus, we suggest that CNTF-driven JAK2 signaling corrects stress-induced reversal learning deficits by modulating the steady-state levels of plasticity-related proteins in the OFC.

Ketamine Corrects a Deficit in Reversal Learning Caused by Chronic Intermittent Cold Stress in Female Rats.

Background: Individuals with stress-related psychiatric disorders exhibit deficits in cognitive flexibility. We have shown that chronic intermittent cold stress induces deficits in reversal learning, a form of cognitive flexibility mediated in the orbitofrontal cortex, that was reversed by ketamine in male rats. Such effects have not been tested in females. In this study, we examined effects of chronic intermittent cold stress and ketamine on reversal learning in females. Methods: Female Sprague-Dawley rats underwent 14 days of chronic intermittent cold and 3 days later received an injection of ketamine (10 mg/kg, i.p.). They were tested on reversal learning 24 hours post-injection. A separate cohort of female rats underwent 14 days of chronic intermittent cold. Three days later they received ketamine and were killed 2 hours post-injection for measurement of the synaptic marker PSD95 in orbitofrontal cortex. Results: Chronic intermittent cold induced a reversal learning deficit in females comparable with that seen in males, which was corrected by ketamine. Moreover, chronic intermittent cold increased PSD95 expression in orbitofrontal cortex, but this increase was not seen in rats receiving ketamine. Conclusions: Chronic intermittent cold stress and ketamine altered reversal learning in female rats similar to effects seen in males. Further, chronic intermittent cold increased PSD95 in orbitofrontal cortex of female rats, indicative of synaptic dysregulation. This effect was attenuated after ketamine administration.