Response of nitrergic system in the brain of rat conditioned to intracranial self-stimulation.

The role of nitrergic system in modulating the action of psychostimulants on reward processing is well established. However, the relevant anatomical underpinnings and scope of the involved interactions with mesolimbic dopaminergic system have not been clarified. Using immunohistochemistry, we track the changes in neuronal nitric oxide synthase (nNOS) containing cell groups in the animals conditioned to intracranial self-stimulation (ICSS) via an electrode implanted in the lateral hypothalamus-medial forebrain bundle (LH-MFB) area. An increase in the nNOS immunoreactivity was noticed in the cells and fibers in the ventral tegmental area (VTA) and nucleus accumbens shell (AcbSh), the primary loci of the reward system. In addition, nNOS was up-regulated in the nucleus accumbens core (AcbC), vertical limb of diagonal band (VDB), locus coeruleus (LC), lateral hypothalamus (LH), superficial gray layer (SuG) of the superior colliculus, and periaqueductal gray (PAG). The brain tissue fragments drawn from these areas showed a change in nNOS mRNA expression, but in opposite direction. Intracerebroventricular (icv) administration of nNOS inhibitor, 7-nitroindazole (7-NI) showed decreased lever press activity in a dose-dependent manner in ICSS task. While an increase in the dopamine (DA) and 3, 4-dihydroxyphenylacetic acid (DOPAC) efflux was noted in the microdialysates collected from the AcbSh of ICSS rats, pre-administration of 7-NI (icv route) attenuated the response. The study identifies nitrergic centers that probably mediate sensory, cognitive, and motor components of the goal-directed behavior.

LSD1-BDNF activity in lateral hypothalamus-medial forebrain bundle area is essential for reward seeking behavior.

Reward induces activity-dependant gene expression and synaptic plasticity-related changes. Lysine-specific histone demethylase 1 (LSD1), a key enzyme driving histone modifications, regulates transcription in neural circuits of memory and emotional behavior. Herein, we focus on the role of LSD1 in modulating the expression of brain derived neurotrophic factor (BDNF), the master regulator of synaptic plasticity, in the lateral hypothalamus-medial forebrain bundle (LH-MFB) circuit during positive reinforcement. Rats, trained for intracranial self-stimulation (ICSS) via an electrode-cannula assembly in the LH-MFB area, were assayed for lever press activity, epigenetic parameters and dendritic sprouting. LSD1 expression and markers of synaptic plasticity like BDNF and dendritic arborization in the LH, showed distinct increase in conditioned animals. H3K4me2 levels at Bdnf IV and Bdnf IX promoters were increased in ICSS-conditioned rats, but H3K9me2 was decreased. While intra LH-MFB treatment with pan Lsd1 siRNA inhibited lever press activity, analyses of LH tissue showed reduction in BDNF expression and levels of H3K4me2 and H3K9me2. However, co-administration of BDNF peptide restored lever press activity mitigated by Lsd1 siRNA. BDNF expression in LH, driven by LSD1 via histone demethylation, may play an important role in reshaping the reward pathway and hold the key to decode the molecular basis of addiction.

Repeated mild traumatic brain injury induces persistent variations in mitochondrial DNA copy number in mesocorticolimbic neurocircuitry of the rat.

Mild traumatic brain injury (MTBI) results in persistent deficits in the cognitive and emotive abilities governed by the mesocorticolimbic (MCL) neurocircuitry. In this study, we observed regional variations in the mitochondrial DNA copy number (mtDNAcn) in the MCL neurocircuitry. Although repeated MTBI (rMTBI) is known to cause mitochondrial dysfunction, the persistent changes in the mtDNAcn and its manifestations in 16S rRNA levels in the MCL neurocircuitry have not been investigated. Herein, we employed the closed head weight drop paradigm to induce rMTBI in rats. We analyzed the mtDNAcn and 16S rRNA levels in eight regions of the MCL neurocircuitry 48 h and 30 days after the rMTBI. The mtDNAcn in the prefrontal cortex, cortex, hippocampus, and ventral tegmental area (VTA) of the rMTBI-exposed rats was decreased at both the time points. Although the mtDNAcn was reduced in hypothalamus and amygdala at 48 h, it was increased at 30 days post rMTBI. The 16S rRNA levels and mtDNAcn were altered in all the regions, with the exception of bed nucleus of stria terminalis and the VTA. Moreover, the rMTBI did not affect the mtDNAcn and 16S rRNA levels in nucleus accumbens. These results suggest that the repetitive trauma induces persistent changes in the mtDNAcn which are manifested as aberrations in mitochondrial transcription in the brain areas crucial for emotion and cognition.

Repeated mild traumatic brain injury affects microbial diversity in rat jejunum.

Traumatic brain injuries (TBI) manifest into post-traumatic stress disorders such as anxiety comorbid with gut ailments. The perturbations in gut microbial communities are often linked to intestinal and neuropsychological disorders. We have previously reported anxiety and abnormalities in gut function in mild TBI (MTBI)-exposed rats. The current study demonstrates the changes in gut microbiome of MTBI-exposed animals and discusses its implications in intestinal health and behaviours. The rats were subjected to repeated MTBI (rMTBI) and microbial composition in jejunum was examined after 6 h, 48 h and 30 days of rMTBI. Significant reduction in bacterial diversity was observed in the rMTBI-exposed animals at all the time points. Principal coordinate analysis based on weighted UniFrac distances indicated substantial differences in gut microbial diversity and abundances in rMTBI-exposed animals as compared to that in healthy controls. The abundance of Proteobacteria increased dramatically with reciprocal decrease in Firmicutes after rMTBI. At the genus level, Helicobacter, Lactobacillus, Campylobacter, and Streptococcus were found to be differentially abundant in the jejunum of rMTBI-exposed rats as compared to sham controls indicating profound dysbiosis from the healthy state. Furthermore, substantial depletion in butyrate-producing bacterial communities was observed in rMTBI-exposed animals. These results suggest that the traumatic stress alters the gut microbiome with possible implications in gut health and neuropsychopathology.