Occlusion of dopamine-dependent synaptic plasticity in the prefrontal cortex mediates the expression of depressive-like behavior and is modulated by ketamine.

Unpredictable chronic mild stress (CMS) is among the most popular protocols used to induce depressive-like behaviors such as anhedonia in rats. Differences in CMS protocols often result in variable degree of vulnerability, and the mechanisms behind stress resilience are of great interest in neuroscience due to their involvement in the development of psychiatric disorders, including major depressive disorder. Expression of depressive-like behaviors is likely driven by long-term alterations in the corticolimbic system and by downregulation of dopamine (DA) signaling. Although we have a deep knowledge about the dynamics of tonic and phasic DA release in encoding incentive salience and in response to acute/chronic stress, its modulatory action on cortical synaptic plasticity and the following implications on animal behavior remain elusive. Here, we show that the expression of DA-dependent synaptic plasticity in the medial prefrontal cortex (mPFC) is occluded in rats vulnerable to CMS, likely reflecting differential expression of AMPA receptors. Interestingly, such difference is not observed when rats are acutely treated with sub-anesthetic ketamine, possibly through the recruitment of dopaminergic nuclei such as the ventral tegmental area. In addition, by applying the synaptic activity sensor SynaptoZip in vivo, we found that chronic stress unbalances the synaptic drive from the infralimbic and prelimbic subregions of the mPFC toward the basolateral amygdala, and that this effect is counteracted by ketamine. Our results provide novel insights into the neurophysiological mechanisms behind the expression of vulnerability to stress, as well as behind the antidepressant action of ketamine.

Facilitation of dopamine-dependent long-term potentiation in the medial prefrontal cortex of male rats follows the behavioral effects of stress.

The effect of stress on animal behavior and brain activity has been attracting growing attention in the last decades. Stress dramatically affects several aspects of animal behavior, including motivation and cognitive functioning, and has been used to model human pathologies such as post-traumatic stress disorder. A key question is whether stress alters the plastic potential of synaptic circuits. In this work, we evaluated if stress affects dopamine (DA)-dependent synaptic plasticity in the medial prefrontal cortex (mPFC). On male adolescent rats, we characterized anxiety- and depressive-like behaviors using behavioral testing before and after exposure to a mild stress (elevated platform, EP). After the behavioral protocols, we investigated DA-dependent long-term potentiation (DA-LTP) and depression (DA-LTD) on acute slices of mPFC and evaluated the activation of DA-producing brain regions by western and dot blot analysis. We show that exposure to the EP stress enhances DA-LTP and that desipramine (DMI) treatment abolishes this effect. We also found that DA-LTD is not affected by EP stress unless when this is followed by DMI treatment. In addition, EP stress reduces anxiety, an effect abolished by both DMI and ketamine, while motivation is promoted by previous exposure to EP stress independently of pharmacological treatments. Finally, this form of stress reduces the expression of the early gene cFOS in the ventral tegmental area. These findings support the idea that mild stressors can promote synaptic plasticity in PFC through a dopaminergic mechanism, an effect that might increase the sensitivity of mPFC to subsequent stressful experiences.