The nucleus accumbens (NAc), ventromedial prefrontal cortex (vmPFC), and cingulate gyrus (Cg) are key regions in the control of mood-related behaviors. Electrical stimulation of these areas induces antidepressant-like effects in both patients and animal models. Another structure whose limbic connections are receiving more interest in the context of mood-related behaviors is the medial part of the subthalamic nucleus (STN). Here, we tested the hypothesis that the mood-related effects of NAc, vmPFC, and Cg are accompanied by changes in the neural activity of the STN. We performed high-frequency stimulation (HFS) of the NAc, vmPFC, and Cg. Animals were behaviorally tested for hedonia and forced swim immobility; and the cellular activities in the different parts of the STN were assessed by means of c-Fos immunoreactivity (c-Fos-ir). Our results showed that HFS of the NAc and vmPFC, but not Cg reduced anhedonic-like and forced swim immobility behaviors. Interestingly, there was a significant increase of c-Fos-ir in the medial STN with HFS of the vmPFC, but not the NAc and Cg as compared to the sham. Correlation analysis showed that the medial STN is associated with the antidepressant-like behaviors in vmPFC HFS animals. No behavioral correlation was found with respect to behavioral outcome and activity in the lateral STN. In conclusion, HFS of the vmPFC induced profound antidepressant-like effects with enhanced neural activity in the medial part of the STN.
Serotonergic (5-HT) drugs are widely used in the clinical management of mood and anxiety disorders. However, it is reported that acute 5-HT treatment elicits anxiogenic-like behavior. Interestingly, the periaqueductal gray (PAG), a midbrain structure which regulates anxiety behavior - has robust 5-HT fibers and reciprocal connections with the hypothalamic-pituitary-adrenal (HPA) axis. Although the HPA axis and the 5-HT system are well investigated, the relationship between the stress hormones induced by 5-HT drug treatment and the PAG neural correlates of the behavior remain largely unknown. In this study, the effects of acute and chronic treatments with buspirone (BUSP) and escitalopram (ESCIT) on anxiety-related behaviors were tested in an open-field (OF). The treatment effects on PAG c-Fos immunoreactivity (c-Fos-ir) and corticosterone (CORT) concentration were measured in order to determine the neural-endocrine correlates of anxiety-related behaviors and drug treatments. Our results demonstrate that acute BUSP and ESCIT treatments induced anxiogenic behaviors with elevation of CORT compared to the baseline. A decrease of c-Fos-ir was found in the dorsomedial PAG region of both the treatment groups. Correlation analysis showed that the CORT were not associated with the OF anxiogenic behavior and PAG c-Fos-ir. No significant differences were found in behaviors and CORT after chronic treatment. In conclusion, acute BUSP and ESCIT treatments elicited anxiogenic response with activation of the HPA axis and reduction of c-Fos-ir in the dorsomedial PAG. Although no correlation was found between the stress hormone and the PAG c-Fos-ir, this does not imply the lack of cause-and-effect relationship between neuroendocrine effects and PAG function in anxiety responses. These correlation studies suggest that the regulation of 5-HT system was probably disrupted by acute 5-HT treatment.
Deep brain stimulation (DBS) is a promising therapy for patients with refractory depression. However, key questions remain with regard to which brain target(s) should be used for stimulation, and which mechanisms underlie the therapeutic effects. Here, we investigated the effect of DBS, with low- and high-frequency stimulation (LFS, HFS), in different brain regions (ventromedial prefrontal cortex, vmPFC; cingulate cortex, Cg; nucleus accumbens (NAc) core or shell; lateral habenula, LHb; and ventral tegmental area) on a variety of depressive-like behaviors using rat models. In the naive animal study, we found that HFS of the Cg, vmPFC, NAc core and LHb reduced anxiety levels and increased motivation for food. In the chronic unpredictable stress model, there was a robust depressive-like behavioral phenotype. Moreover, vmPFC HFS, in a comparison of all stimulated targets, produced the most profound antidepressant effects with enhanced hedonia, reduced anxiety and decreased forced-swim immobility. In the following set of electrophysiological and histochemical experiments designed to unravel some of the underlying mechanisms, we found that vmPFC HFS evoked a specific modulation of the serotonergic neurons in the dorsal raphe nucleus (DRN), which have long been linked to mood. Finally, using a neuronal mapping approach by means of c-Fos expression, we found that vmPFC HFS modulated a brain circuit linked to the DRN and known to be involved in affect. In conclusion, HFS of the vmPFC produced the most potent antidepressant effects in naive rats and rats subjected to stress by mechanisms also including the DRN.
The electrical stimulation of specific brain targets has been shown to induce striking antidepressant effects. Despite that recent data have indicated that cerebellum is involved in emotional regulation, the mechanisms by which stimulation improved mood-related behaviors in the cerebellum remained largely obscure. Here, we investigated the stimulation effects of the ventromedial prefrontal cortex (vmPFC), nucleus accumbens (NAc), and lateral habenular nucleus on the c-Fos neuronal activity in various deep cerebellar and vestibular nuclei using the unpredictable chronic mild stress (CMS) animal model of depression. Our results showed that stressed animals had increased number of c-Fos cells in the cerebellar dentate and fastigial nuclei, as well as in the spinal vestibular nucleus. To examine the stimulation effects, we found that vmPFC stimulation significantly decreased the c-Fos activity within the cerebellar fastigial nucleus as compared to the CMS sham. Similarly, there was also a reduction of c-Fos expression in the magnocellular part of the medial vestibular nucleus in vmPFC- and NAc core-stimulated animals when compared to the CMS sham. Correlational analyses showed that the anxiety measure of home-cage emergence escape latency was positively correlated with the c-Fos neuronal activity of the cerebellar fastigial and magnocellular and parvicellular parts of the interposed nuclei in CMS vmPFC-stimulated animals. Interestingly, there was a strong correlation among activation in these cerebellar nuclei, indicating that the antidepressant-like behaviors were possibly mediated by the vmPFC stimulation-induced remodeling within the forebrain-cerebellar neurocircuitry.
Deep brain stimulation (DBS) has gained interest as a potential therapy for advanced treatment-resistant dementia. However, possible targets for DBS and the optimal stimulation parameters are not yet clear. Here, we compared the effects of DBS of the CA1 sub-region of the hippocampus, mammillothalamic tract, anterior thalamic nucleus, and entorhinal cortex in an experimental rat model of dementia. Rats with scopolamine-induced amnesia were assessed in the object location task with different DBS parameters. Moreover, anxiety-related side effects were evaluated in the elevated zero maze and open field. After sacrifice, we applied c-Fos immunohistochemistry to assess which memory-related regions were affected by DBS. When comparing all structures, DBS of the entorhinal cortex and CA1 sub-region was able to restore memory loss when a specific set of stimulation parameters was used. No anxiety-related side effects were found following DBS. The beneficial behavioral performance of CA1 DBS rats was accompanied with an activation of cells in the anterior cingulate gyrus. Therefore, we conclude that acute CA1 DBS restores memory loss possibly through improved attentional and cognitive processes in the limbic cortex.
Major depression contributes significantly to the global disability burden. Since the first clinical study of deep brain stimulation (DBS), over 406 patients with depression have now undergone this neuromodulation therapy, and 30 animal studies have investigated the efficacy of subgenual cingulate DBS for depression. In this review, we aim to provide a comprehensive overview of the progress of DBS of the subcallosal cingulate in humans and the medial prefrontal cortex, its rodent homolog. For preclinical animal studies, we discuss the various antidepressant-like behaviors induced by medial prefrontal cortex DBS and examine the possible mechanisms including neuroplasticity-dependent/independent cellular and molecular changes. Interestingly, the response rate of subcallosal cingulate Deep brain stimulation marks a milestone in the treatment of depression. DBS among patients with treatment-resistant depression was estimated to be approximately 54% across clinical studies. Although some studies showed its stimulation efficacy was limited, it still holds great promise as a therapy for patients with treatment-resistant depression. Overall, further research is still needed, including more credible clinical research, preclinical mechanistic studies, precise selection of patients, and customized electrical stimulation paradigms.
Electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) in rats has been shown to elicit panic-like behaviour and can be a useful as an unconditioned stimulus for modelling anticipatory fear and agoraphobia in a contextual fear conditioning paradigm. In this study, we further analysed our previous data on the effects of escitalopram (a selective serotonin reuptake inhibitor, SSRI) and buspirone (a 5-HT1A receptor partial agonist) on dlPAG-induced anticipatory fear behaviour in a rat model using freezing as a measure. We then attempted to unravel some of the interactions with dopamine signalling using tyrosine hydroxylase (TH) immunohistochemistry to probe the effects on dopaminergic neurons. We showed that acute treatment of escitalopram, but not buspirone, was effective in reducing anticipatory freezing behaviour, while chronic administrations of both drugs were effective. We found that the dlPAG stimulation induced increase number of dopaminergic neurons in the ventral tegmental area (VTA) which was reversed in both chronic buspirone and escitalopram groups. We further found a strong positive correlation between the number of dopaminergic neurons and freezing in the VTA and showed positive correlations between dopaminergic neurons in the VTA and substantia nigra pars compacta (SNpc) in escitalopram and buspirone groups, respectively. Overall, we showed that chronic treatment with an SSRI and a 5-HT1A agonist reduced anticipatory freezing behaviour which seems to be associated, through correlative studies, with a reversal of dlPAG stimulation induced increase in number of dopaminergic neurons in the VTA and/or SNpc.