Chronic stress is a risk factor for many psychopathological conditions, including depression and anxiety disorders. Cognitive impairments associated with prefrontal cortical dysfunction are a major component of such illnesses. Using an attentional set shifting test (AST), we have previously shown that elevating noradrenergic activity in rat medial prefrontal cortex (mPFC) can facilitate cognitive set-shifting, and that chronic unpredictable stress (CUS) caused set-shifting deficits. It is not known, however, if noradrenergic modulatory function is compromised by chronic stress, perhaps contributing to the stress-induced cognitive deficit. Thus, the first study investigated whether acutely elevating noradrenergic activity in mPFC still enhances cognitive function after chronic stress. As previously demonstrated, CUS impaired cognitive set-shifting on the AST. This deficit was abolished by acute systemic administration of the α2-adrenergic autoreceptor antagonist, atipamezole. Microdialysis revealed no differences in extracellular norepinephrine (NE) levels in mPFC of CUS-exposed and unstressed control rats at baseline or during behavioral testing, and comparable increases after atipamezole. In the second experiment, rats were treated chronically with the selective NE reuptake blocker, desipramine, during the CUS treatment through behavioral testing. Again, CUS impaired cognitive set-shifting in vehicle-treated rats, and chronic desipramine treatment prevented such deficits. Acute blockade of post-synaptic α1-adrenergic receptors in mPFC prior to testing blocked the beneficial effect of desipramine on cognitive set-shifting. These results suggest that desipramine restores cognitive set-shifting capability that has been compromised by chronic stress by activating α1-adrenergic receptors in the mPFC. Thus, noradrenergic modulatory capability in mPFC remains intact after CUS, and this represents one possible substrate by which antidepressants may exert their beneficial effects in the treatment of depression.

Deficits in cognitive flexibility, the ability to modify behavior in response to changes in the environment, contribute to the onset and maintenance of stress-related neuropsychiatric illnesses, such as depression. Cognitive flexibility depends on medial prefrontal cortex (mPFC) function, and in depressed patients, cognitive inflexibility is associated with hypoactivity and decreased glutamate receptor expression in the mPFC. Rats exposed to chronic unpredictable stress (CUS) exhibit compromised mPFC function on the extradimensional (ED) set-shifting task of the attentional set-shifting test. Moreover, CUS-induced ED deficits are associated with dendritic atrophy and decreased glutamate receptor expression in the mPFC. This evidence suggests that impaired glutamate signaling may underlie stress-induced deficits in cognitive flexibility. To test this hypothesis, we first demonstrated that blocking NMDA or AMPA receptors in the mPFC during ED replicated CUS-induced deficits in naïve rats. Secondly, we found that expression of activity-regulated cytoskeleton-associated protein (Arc) mRNA, a marker of behaviorally induced glutamate-mediated plasticity, was increased in the mPFC following ED. We then showed that CUS compromised excitatory afferent activation of the mPFC following pharmacological stimulation of the mediodorsal thalamus (MDT), indicated by a reduced induction of c-fos expression. Subsequently, in vivo recordings of evoked potentials in the mPFC indicated that CUS impaired afferent activation of the mPFC evoked by MDT stimulation, but not the ventral hippocampus. Lastly, glutamate microdialysis, showed that CUS attenuated the acute stress-evoked increase in extracellular glutamate in the mPFC. Together, these results demonstrate that CUS-induced ED deficits are associated with compromised glutamate neurotransmission in the mPFC.

Rationale Acute low-dose administration of the NMDA receptor antagonist, ketamine, produces rapid and sustained antidepressant-like effects in humans and rodents. Recently, we found that the long-lasting effect of ketamine on the forced swim test requires ventral hippocampal (vHipp) activity at the time of drug administration. The medial prefrontal cortex (mPFC), a target of the vHipp dysregulated in depression, is important for cognitive flexibility and response strategy selection. Deficits in cognitive flexibility, the ability to modify thoughts and behaviors in response to changes in the environment, are associated with depression. We have shown that chronic stress impairs cognitive flexibility on the attentional set-shifting test (AST), and induces a shift from active to passive response strategies on the shock-probe defensive burying test (SPDB). Objective In this study, we tested the effects of ketamine on chronic stress-induced changes in cognitive flexibility and coping behavior on the AST and SPDB, respectively. Subsequently, we investigated vHipp-mPFC plasticity as a potential mechanism of ketamine’s therapeutic action. Results Ketamine reversed deficits in cognitive flexibility and restored active coping behavior in chronically stressed rats. Further, high frequency stimulation in the vHipp replicated ketamine’s antidepressant-like effects on the forced swim test and AST, but not on the SPDB. Conclusion These results show that ketamine restores cognitive flexibility and coping response strategy compromised by stress. Activity in the vHipp-mPFC pathway may represent a neural substrate for some of the antidepressant-like behavioral effects of ketamine, including cognitive flexibility, but other circuits may mediate the effects of ketamine on coping response strategy.

Cognitive impairment, particularly involving dysfunction of circuitry within the prefrontal cortex (PFC), represents a core feature of many neuropsychiatric and neurodevelopmental disorders, including depression, post-traumatic stress disorder, schizophrenia and autism spectrum disorder. Deficits in cognitive function also represent the most difficult symptom domain to successfully treat, as serotonin reuptake inhibitors and tricyclic antidepressants have only modest effects. Functional neuroimaging studies and postmortem analysis of human brain tissue implicate the PFC as being a primary region of dysregulation in patients with these disorders. However, preclinical behavioral assays used to assess these deficits in mouse models which can be readily manipulated genetically and could provide the basis for studies of new treatment avenues have been underutilized. Here we describe the adaptation of a behavioral assay, the attentional set shifting task (AST), to be performed in mice to assess prefrontal cortex mediated cognitive deficits. The neural circuits underlying behavior during the AST are highly conserved across humans, nonhuman primates and rodents, providing excellent face, construct and predictive validity.

Cognitive impairments associated with dysfunction of the medial prefrontal cortex (mPFC) are prominent in stress-related psychiatric disorders. We have shown that enhancing noradrenergic tone acutely in the rat mPFC facilitated extra-dimensional (ED) set-shifting on the attentional set-shifting test (AST), whereas chronic unpredictable stress (CUS) impaired ED. In this study, we tested the hypothesis that the acute facilitatory effect of norepinephrine (NE) in mPFC becomes detrimental when activated repeatedly during CUS. Using microdialysis, we showed that the release of NE evoked in mPFC by acute stress was unchanged at the end of CUS treatment. Thus, to then determine if repeated elicitation of this NE activity in mPFC during CUS may have contributed to the ED deficit, we infused a cocktail of a 1 -, b 1 -, and b 2 -adrenergic receptor antagonists into the mPFC prior to each CUS session, then tested animals drug free on the AST. Antagonist treatment prevented the CUS-induced ED deficit, suggesting that NE signaling during CUS compromised mPFC function. We confirmed that this was not attributable to sensitization of adrenergic receptor function following chronic antagonist treatment, by administering an additional microinjection into the mPFC immediately prior to ED testing. Acute antagonist treatment did not reverse the beneficial effects of chronic drug treatment during CUS, nor have any effect on baseline ED performance in chronic vehicle controls. Thus, we conclude that blockade of noradrenergic receptors in mPFC protected against the detrimental cognitive effects of CUS, and that repeated elicitation of noradrenergic facilitatory activity is one mechanism by which chronic stress may promote mPFC cognitive dysfunction.

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Background Phosphatidylethanol 16:0/18:1 (PEth), found in whole blood, is a biomarker for alcohol consumption with high sensitivity, specificity, and a long detection window. The TASSO‐M20 device is used to self‐collect capillary blood from the upper arm and has advantages over finger stick methods. The purpose of this study was to (1) validate PEth measurement using the TASSO‐M20 device, (2) describe the TASSO‐M20 for blood self‐collection during a virtual intervention, and (3) characterize PEth, urinary ethyl glucuronide (uEtG) and self‐reported alcohol in a single participant over time. Methods PEth levels in blood samples dried on TASSO‐M20 plugs were compared to those in (1) liquid whole blood (N = 14) and (2) dried blood spot cards (DBS; N = 23). Additionally, the self‐reported drinking, positive or negative uEtG results (dip card cutoff ≥300 ng/mL), and observed self‐collection of blood with TASSO‐M20 devices for PEth levels were obtained over time during virtual interviews of a single contingency management participant. High‐performance liquid chromatography with tandem mass spectrometry detection was used to measure PEth levels for both preparations. Results PEth concentrations from dried blood on TASSO‐M20 plugs and liquid whole blood were correlated (0 to 1700 ng/mL; N = 14; r2 = 0.988; slope = 0.951) and in a subgroup of samples with lower concentrations (N = 7; 0 to 200 ng/mL; r2 = 0.944, slope = 0.816). PEth concentrations from dried blood on TASSO‐M20 plugs and DBS were correlated (0 to 2200 ng/mL; N = 23; r2 = 0.927; slope = 0.667) and in a subgroup of samples with lower concentrations (N = 16; 0 to 180 ng/mL; r2 = 0.978, slope = 0.749). Results of the contingency management participant indicate that changes in PEth levels (TASSO‐M20) and uEtG concentrations were consistent with each other and with changes in self‐reported alcohol use. Conclusions Our data support the utility, accuracy, and feasibility of using the TASSO‐M20 device for blood self‐collection during a virtual study. The TASSO‐M20 device had multiple advantages over the typical finger stick method, including consistent blood collection, participant acceptability, and less discomfort as indicated by acceptability interviews.