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Byline: Sneha. Sagarkar, Deepa. Gandhi, S. Devi, Amul. Sakharkar, Atya. Kapley Objective: Chronic exposure to atrazine and other pesticides is reported to cause metabolic disorders, yet information on effects of [...]

Introduction: Repeated traumatic events result in long-lasting neuropsychiatric ailments, including neuroendocrine imbalances. Neuropeptide Y (NPY) in the arcuate nucleus (Arc) is an important orexigenic peptide. However, the molecular underpinnings of its dysregulation owing to traumatic brain injury remain unknown. Methods: Rats were subjected to repeated mild traumatic brain injury (rMTBI) using the closed head weight-drop model. Feeding behavior and the regulatory epigenetic parameters of NPY expression were measured at 48 h and 30 days post-rMTBI. Further, sodium butyrate (SB), a pan-histone deacetylase (HDAC) inhibitor, was administered to examine whether histone deacetylation is involved in NPY expression post-rMTBI. Results: The rMTBI attenuated food intake, which was coincident with a decrease in NPY mRNA and protein levels in the Arc post-rMTBI. Further, rMTBI also reduced the mRNA levels of the cAMP response element-binding protein (CREB) and CREB-binding protein (CBP) and altered the mRNA levels of the various isoforms of the HDACs. Concurrently, the acetylated histone 3-lysine 9 (H3-K9) levels and the binding of CBP at the NPY promoter in the Arc of the rMTBI-exposed rats were reduced. However, the treatment with SB corrected the rMTBI-induced deficits in the H3-K9 acetylation levels and CBP occupancy at the NPY promoter, restoring both NPY expression and food intake. Conclusions: These findings suggest that histone deacetylation at the NPY promoter persistently controls NPY function in the Arc after rMTBI. This study also demonstrates the efficacy of HDAC inhibitors in mitigating trauma-induced neuroendocrine maladaptations in the hypothalamus. [ABSTRACT FROM AUTHOR]

Thyrotropin‐releasing hormone (TRH) regulates the hypothalamic–pituitary–thyroid axis in mammals and also regulates prolactin secretion, directly or indirectly via tuberoinfundibular dopamine neurons. Although TRH is abundantly expressed in teleost brain and believed to mediate neuronal communication, empirical evidence is lacking. We analyzed pro‐TRH‐mRNA expression, mapped TRH‐immunoreactive elements in the brain and pituitary, and explored its role in regulation of hypophysiotropic dopamine (DA) neurons in the catfish, Clarias batrachus. Partial pro‐TRH transcript from C. batrachus transcriptome showed six TRH progenitors repeats. Quantitative real‐time polymerase chain reaction (qRT‐PCR) identified pro‐TRH transcript in a number of different brain regions and immunofluorescence showed TRH‐immunoreactive cells/fibers in the olfactory bulb, telencephalon, preoptic area (POA), hypothalamus, midbrain, hindbrain, and spinal cord. In the pituitary, TRH‐immunoreactive fibers were seen in the neurohypophysis, proximal pars distalis, and pars intermedia but not rostral pars distalis. In POA, distinct TRH‐immunoreactive cells/fibers were seen in nucleus preopticus periventricularis anterior (NPPa) that demonstrated a significant increase in TRH‐immunoreactivity when collected during preparatory and prespawning phases, reaching a peak in the spawning phase. Although tyrosine hydroxylase (TH)‐immunoreactive neurons in NPPa are hypophysiotropic, none of the TRH‐immunoreactive neurons in NPPa accumulated neuronal tracer DiI following implants into the pituitary. However, 87 ± 1.6% NPPa TH‐immunoreactive neurons were surrounded by TRH‐immunoreactive axons that were seen in close proximity to the somata. Superfused POA slices treated with TRH (0.5–2 μM) significantly reduced TH concentration in tissue homogenates and the percent TH‐immunoreactive area in the NPPa. We suggest that TRH in the brain of C. batrachus regulates a range of physiological functions but in particular, serves as a potential regulator of hypophysiotropic DA neurons and reproduction. Organization of TRH‐immunoreactive elements was studied in the brain and pituitary of the catfish. A distinct population of TRH neurons resides in preoptic area (POA) and demonstrated reproduction phase‐dependent changes and interaction with hypophysiotropic dopamine neurons. TRH may serve as potential regulator of POA dopamine neurons and reproduction. [ABSTRACT FROM AUTHOR]

Although chronic nicotine administration does not affect memory, its withdrawal causes massive cognitive deficits. The underlying mechanisms, however, have not been understood. We test the role of cocaine- and amphetamine-regulated transcript peptide (CART), a neuropeptide known for its procognitive properties, in this process. The mice on chronic nicotine treatment/withdrawal were subjected to novel object recognition task. The capability of the animal to discriminate between the novel and familiar objects was tested and represented as discrimination index (DI); reduction in the index suggested amnesia. Nicotine for 49 days had no effect on DI, but 8-hour withdrawal caused a significant reduction, followed by full recovery at 24-hour withdrawal timepoint. Bilateral CART infusion in dorsal hippocampus rescued deficits in DI at 8-hours, whereas CART-antibody infusion into the dorsal hippocampus attenuated the recovery at 24-hours. Commensurate changes were observed in the CART as well as CART mRNA profiles in the hippocampus. CART mRNA expression and the peptide immunoreactivity did not change significantly following chronic nicotine treatment. However, there was a significant reduction at 8-hour withdrawal, followed by a drastic increase in CART immunoreactivity as well as CART mRNA at 24-hour withdrawal, compared with 8-hour withdrawal. Distinct α7-nicotinic receptor immunoreactivity was detected on the hippocampal CART neurons, suggesting cholinergic inputs. An increase in the synaptophysin immunoreactive elements around CART cells in the dentate gyrus, cornu ammonis 3 and subiculum at 24-hour post-withdrawal timepoint suggested neuronal plasticity. CART circuit dynamics in the hippocampus seems to modulate short-term memory associated with nicotine withdrawal. [ABSTRACT FROM AUTHOR]

Cocaine- and amphetamine- regulated transcript (CART) and Neuropeptide Y (NPY) primarily regulate energy homeostasis. Anurans exhibit diurnal behavioral rhythm, but the response of central neuropeptides to the Day-Night cycle is not elucidated. In this study, we have examined the profile of CART and NPY in the brain of Euphlyctis cyanophlyctis from 6:00 h to 24:00 h. Although expressions of CART and NPY changed with time of the day, circadian oscillation was observed only in expression of CART in anteroventral tegmentum (AV). CART exhibited a single peak in preoptic area (POA), Edinger-Westphal nucleus (EW), nucleus isthmus (NI) and raphe nucleus (Ra); two peaks in ventral hypothamalus (vHy), habenula (Hb) and torus semicircularis (TS). NPY exhibited single peak in TS and suprachiasmatic nucleus (SCN); two peaks in POA, vHy, AV and EW. The daily modulations of these neuropeptides may contribute to their physiological activities and are evolutionarily conserved. [ABSTRACT FROM AUTHOR]

Although the role of cocaine- and amphetamine-regulated transcript peptide (CART) in modulating the mesolimbic reward pathway has been suggested, underlying cellular mechanisms have not been elucidated. Herein, we investigate the involvement of G i/o dependent protein kinase A (PKA)/extracellular signal-regulated kinase (ERK)/cAMP response element binding protein (CREB) signaling in CART induced reward behavior. The rat was implanted with a stimulating electrode targeted at the lateral hypothalamus (LH)-medial forebrain bundle (MFB) and conditioned to intracranial self-stimulation (ICSS) in an operant chamber. Intracerebroventricular (icv) administration of CART (55-102) dose-dependently lowered ICSS threshold suggesting reward promoting action, however, pretreatment with subeffective doses of G i/o inhibitor (pertussis toxin, PTX) or PKA inhibitor (Rp-cAMPS) or ERK inhibitor (U0126) via icv route, attenuated CART mediated reward experience. Operant conditioned rats showed increased pCREB levels in the nucleus accumbens shell (AcbSh), ventral tegmental area (VTA) and hypothalamic paraventricular nucleus (PVN). Infusion of CART (icv) in the conditioned rats augmented the population of pCREB positive cells in the AcbSh, VTA and PVN areas, but not in the arcuate nucleus (ARC). Pretreatment with U0126 significantly decreased CART induced pCREB activation in the AcbSh and VTA, but not in PVN and ARC. ICSS or CART induced CREB mRNA expression in Acb and VTA was attenuated by U0126. We suggest that recruitment of G i/o dependent PKA/ERK/CREB phosphorylation signaling in Acb and VTA might play an important role in CART induced reward behavior., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Of all types of injuries, traumatic brain injuries (TBIs) are most likely to result in death or permanent physical or mental disabilities. With the increased frequency of military operations, terror attacks, sports activities, and road mishaps, TBIs are increasingly becoming a serious public health concern. Patients who meet with moderate-to-severe TBI suffer from a constellation of cognitive deficits and phenotypes due to diffuse axonal injury. On the contrary, minimal TBI precipitates in long-term behavioral complications commonly referred to as post-traumatic stress disorders, which consist of depression, anxiety, hallucinations, and so on. During the last decade, epigenetic mechanisms, such as histone posttranslational modifications, DNA methylation, and noncoding RNAs, have received reasonable attention by scientists studying the neurobiology of TBI. Chromatin remodeling sculpted by various epigenetic factors in different parts of the brain controls many intricate processes involved in important neural functions. Although stable and dogmatic, the reversible nature of epigenetic modifications has attracted special attention for their emerging potential in therapeutic development. Herein, we offer an overview of recent observations on epigenetic pathways that are likely involved in shaping neural function and maintain the state of neuropathology in response to traumatic events., (Copyright © 2018. Published by Elsevier Inc.)