Chemogenetic Inhibition of Infralimbic Prefrontal Cortex GABAergic Parvalbumin Interneurons Attenuates the Impact of Chronic Stress in Male Mice

Abstract

Hypofunction of the prefrontal cortex (PFC) contributes to stress-related neuropsychiatric illnesses. Mechanisms leading to prefrontal hypoactivity remain to be determined. Prior evidence suggests that chronic stress leads to an increase in activity of parvalbumin (PV) expressing GABAergic interneurons (INs) in the PFC. The purpose of the study was to determine whether reducing PV IN activity in the Infralimbic (IL) PFC would prevent stress-related phenotypes. We used a chemogenetic approach to inhibit IL PFC PV INs during stress. Mice were first tested in the tail suspension test (TST) to determine the impact of PV IN inhibition on behavioral responses to acute stress. The long-term impact of PV IN inhibition during a modified chronic variable stress (CVS) was tested in the forced swim test (FST). Acute PV IN inhibition reduced active (struggling) and increased passive coping behaviors (immobility) in the TST. In contrast, inhibition of PV INs during CVS increased active and reduced passive coping behaviors in the FST. Moreover, chronic inhibition of PV INs attenuated CVS-induced changes in Fos expression in the prelimbic cortex (PrL), basolateral amygdala (BLA), and ventrolateral periaqueductal gray (vlPAG) and also attenuated adrenal hypertrophy and body weight loss associated with chronic stress. Our results suggest differential roles of PV INs in acute versus chronic stress, indicative of distinct biological mechanisms underlying acute versus chronic stress responses. Our results also indicate a role for PV INs in driving chronic stress adaptation and support literature evidence suggesting cortical GABAergic INs as a therapeutic target in stress-related illnesses.

Effects of Biological Sex and Stress Exposure on Ventromedial Prefrontal Regulation of Mood-Related Behaviors

“…Created with BioRender.com. (Nawreen et al, 2020). Furthermore, chronic stress increases GAD67 mRNA in the male mouse IL (Shepard et al, 2016).…”

The DREADDful Hurdles and Opportunities of the Chronic Chemogenetic Toolbox

“…Nonetheless, low doses of CNO (≤3 mg/kg bodyweight) are reported to result in subthreshold clozapine concentrations that are unlikely to bind with endogenous receptors, as the affinity of clozapine for DREADDs is much higher [ 14 , 17 , 18 , 19 ]. Although many studies demonstrated the absence of behavioral off-target effects induced by CNO or back-metabolized clozapine in animals without DREADD expression [ 20 , 21 , 22 , 23 , 24 , 25 ], other ligands have been developed to overcome this concern—e.g., olanzapine [ 26 ], perlapine [ 27 ], compound 21 [ 27 ], deschloroclozapine [ 28 ], and JHU37160/152 [ 29 ] ( Figure 1 e). The absence of off-target effects of these new generation of DREADD actuators also remains to be demonstrated.…”

“…This is underscored by studies comparing results obtained from acute and chronic DREADD applications. Although some of those experiments show a similar level of neuronal activity or behavioral outcomes [ 22 , 49 ], many others report null or antagonistic effects upon continuous DREADD activation [ 21 , 22 , 23 , 36 , 37 , 38 , 41 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ] ( Table 1 ). Given these discrepancies, it is clear that there is no straightforward way to extrapolate study results of acute experiments to chronic experiments and more fundamental knowledge of chronic neuromodulation is of key importance.…”

Avaliação do nicho neurogênico hipocampal adulto em camundongos machos geneticamente modificados para a não expressão de fatores pro-inflamatórios (iNOS) ou anti-inflamatórios (IL-10) submetidos a um protocolo de estresse crônico

“…Chronic treatment with escitalopram did not modify the neurogenic and behavioral changes observed in these animals. Considering that parvalbumin (PV) interneurons in the prefrontal cortex are also capable of modulating depressive-and anxiety-like behaviors (Fogaça et al, 2020;Nawreen et al, 2020;, we decided to investigate the impact of iNOS deletion in another region and cell population associated with these changes. We observed that neither PV density nor their recruitment was affected by our manipulation.…”

“…Além disso, também foi demonstrado que a estimulação elétrica subconvulsivante do PrL evoca respostas de enfrentamento ativo no FST em uma linhagem de ratos depressivos (DRL-do inglês "depressive rat line"). Dessa SIERRA- MERCADO et al, 2011;NAWREEN et al, 2020).…”