Reversal of stress-induced dendritic atrophy in the prefrontal cortex by intracranial self-stimulation

Abstract

The mammalian prefrontal cortex (PFC) has been implicated in a variety of motivational and emotional processes underlying working memory, attention and decision making. The PFC receives dopaminergic projections from the ventral tegmental area (VTA) and contains high density of D1 and D2 receptors and these projections are important in higher integrative cortical functions. The neurons of the PFC have been shown to undergo atrophy in response to stress. In an earlier study, we demonstrated that the chronic stress-induced atrophy of hippocampal neurons and behavioral impairment in the T-maze task were reversed by the activation of dopaminergic pathway by intracranial self-stimulation (ICSS) of the VTA. The stress-induced decrease in hippocampal dopamine (DA) levels was also restored by ICSS. Whether the reversal of stress-induced behavioral deficits by ICSS involves changes in the morphology of PFC neurons is unknown and the current study addresses this issue. Male Wistar rats underwent 21 days of restraint stress followed by ICSS for 10 days. The dendritic morphology of the PFC neurons was studied in Golgi-impregnated sections. Stress produced atrophy of the layer II/III and V PFC pyramidal neurons and ICSS to naïve rats significantly increased the dendritic arborization of these neurons compared to control. Interestingly, ICSS of stressed rats resulted in the reversal of the dendritic atrophy. Further, these structural changes were associated with a restored tissue levels of DA, norepinephrine and serotonin in the PFC. These results indicate that the behavioral restoration in stressed rats could involve changes in the plasticity of the PFC neurons and these results further our understanding of the role of dopaminergic neurotransmitter system in the amelioration of stress-induced deficits.

D1 receptors regulate dendritic morphology in normal and stressed prelimbic cortex

“…Our data from unstressed rats suggest that D1R activation is necessary for dendritic maintenance; thus, preventing downregulation of baseline dopamine release in mPFC could prevent stress-induced dendritic retraction. This is consistent with the recent finding that intracranial self-stimulation of the ventral tegmental area after stress restores baseline levels of mPFC dopamine and apical dendritic morphology (Ramkumar et al, 2012). Future studies measuring baseline levels of dopamine in mPFC could determine whether D1R blockade in PL during stress prevents stress-induced downregulation of dopamine release in mPFC.…”

“…On the other hand, chronic stress reduces baseline dopamine levels in mPFC (Gresch et al, 1994; Ramkumar et al, 2012). Blockade of D1Rs during stress may prevent stress-induced downregulation of dopamine release in mPFC.…”

Effects of repeated yohimbine administration on reinstatement of palatable food seeking: involvement of dopamine D1-like receptors and food-associated cues

“…Chronic stress reduces the number of active dopamine cells in ventral tegmental area (Moore et al, 2001), resulting in reduced baseline dopamine levels in mPFC (Gresch et al, 1994; Mizoguchi et al, 2008; Mizoguchi et al, 2000; Ramkumar et al, 2012) and a compensatory increase in D 1 Rs in mPFC (Mizoguchi et al, 2000). Given that yohimbine-induced reinstatement of food seeking requires activation of D 1 Rs in mPFC (Nair et al, 2011) and that acute stressors, including yohimbine (Chen et al, 2014; Tanda et al, 1996), selectively increase dopamine in the mPFC—an effect that is sensitized in chronically stressed animals (Di Chiara et al, 1999; Gresch et al, 1994)—we speculate that the enhanced yohimbine-induced responding observed in saline + yohimbine rats in Experiment 1 was due to augmented D 1 R activation in mPFC relative to controls.…”

“…This prediction was supported in the present study in that SCH-23390-treated rats displayed increased responding during extinction training and yohimbine-induced reinstatement tests, but only in Experiment 2, when discrete food cues were available. Although chronic stress also has been shown to cause an increase in D 1 Rs in mPFC (Mizoguchi et al, 2000), this is superimposed on a background of reduced basal dopamine levels (Gresch et al, 1994; Mizoguchi et al, 2008; Mizoguchi et al, 2000; Ramkumar et al, 2012), and thus should only invigorate responding under conditions of stimulated dopamine release. This prediction was supported in the present study in that chronically stressed rats showed low baseline levels of responding and increased yohimbine-primed responding in both Experiments 1 and 2.…”

Galanin mediates features of neural and behavioral stress resilience afforded by exercise

“…Inactivation of the mPFC also reverses the anxiolytic effects of environmental enrichment (Lehmann and Herkenham, 2011) and protective effect of behavioral control over stress (Amat et al, 2005), although not all forms of resilience are PFC-dependent (Greenwood et al, 2013). Dendritic spines, the morphological hallmark of excitatory synapses, are reduced in the mPFC after stress (Leuner and Shors, 2012; Radley and Morrison, 2005), whereas antidepressants (Bessa et al, 2009) or intracranial self-stimulation (Ramkumar et al, 2011) prevent stress- induced alterations in dendritic structure. Consistent with these data, clinical literature shows that resilient individuals exhibit greater mPFC activation (New et al, 2009; Peres et al, 2011), while susceptible individuals exhibit impaired mPFC-to-amygdala functional connectivity (Bremner et al, 1999; Tromp et al, 2012).…”