Nucleus accumbens myocyte enhancer factor 2C mediates the maintenance of peripheral nerve injury-induced physiological and behavioral maladaptations.

Preclinical and clinical work has demonstrated altered plasticity and activity in the nucleus accumbens (NAc) under chronic pain states, highlighting critical therapeutic avenues for the management of chronic pain conditions. In this study, we demonstrate that myocyte enhancer factor 2C (MEF2C), a master regulator of neuronal activity and plasticity, is repressed in NAc neurons after prolonged spared nerve injury (SNI). Viral-mediated overexpression of Mef2c in NAc neurons partially ameliorated sensory hypersensitivity and emotional behaviors in mice with SNI, while also altering transcriptional pathways associated with synaptic signaling.

RGS4 Actions in Mouse Prefrontal Cortex Modulate Behavioral and Transcriptomic Responses to Chronic Stress and Ketamine.

The signal transduction protein, regulator of G protein signaling 4 (RGS4), plays a prominent role in physiologic and pharmacological responses by controlling multiple intracellular pathways. Our earlier work identified the dynamic but distinct roles of RGS4 in the efficacy of monoamine-targeting versus fast-acting antidepressants. Using a modified chronic variable stress (CVS) paradigm in mice, we demonstrate that stress-induced behavioral abnormalities are associated with the downregulation of RGS4 in the medial prefrontal cortex (mPFC).

Microglial Engulfment of Spines in the Ventral Zona Incerta Regulates Anxiety-Like Behaviors in a Mouse Model of Acute Pain.

Although activation of microglial cells is critical in developing brain disorders, their role in anxiety-like behaviors in pain is still vague. This study indicates that alteration of microglia's neuronal spine engulfment capacity in ventral zona incerta (ZI ) leads to significant pain and anxiety-like behaviors in mice 1-day post-injection of Complete Freud's Adjuvant (CFA1D). Performing whole-cell patch-clamp recordings in GABAergic neurons in the ZI (ZI ) in brain slices, we observed decreased activity in ZIv and reduced frequency of the miniature excitatory postsynaptic currents (mEPSCs) in ZI of CFA1D mice compared with the saline1D mice.

Early-life inflammation promotes depressive symptoms in adolescence via microglial engulfment of dendritic spines.

Early-life inflammation increases the risk for depression in later life. Here, we demonstrate how early-life inflammation causes adolescent depressive-like symptoms: by altering the long-term neuronal spine engulfment capacity of microglia. For mice exposed to lipopolysaccharide (LPS)-induced inflammation via the Toll-like receptor 4/NF-κB signaling pathway at postnatal day (P) 14, ongoing longitudinal imaging of the living brain revealed that later stress (delivered during adolescence on P45) increases the extent of microglial engulfment around anterior cingulate cortex (ACC) glutamatergic neuronal (ACC) spines.

Distinct thalamocortical circuits underlie allodynia induced by tissue injury and by depression-like states.

In humans, tissue injury and depression can both cause pain hypersensitivity, but whether this involves distinct circuits remains unknown. Here, we identify two discrete glutamatergic neuronal circuits in male mice: a projection from the posterior thalamic nucleus (PO) to primary somatosensory cortex glutamatergic neurons (S1) mediates allodynia from tissue injury, whereas a pathway from the parafascicular thalamic nucleus (PF) to anterior cingulate cortex GABA-containing neurons to glutamatergic neurons (ACC) mediates allodynia associated with a depression-like state. In vivo calcium imaging and multi-tetrode electrophysiological recordings reveal that PO and PF populations undergo different adaptations in the two conditions.

Role of Orexin-1 Receptor Within the Ventral Tegmental Area in Mediating Stress- and Morphine Priming-induced Reinstatement of Conditioned Place Preference in Rats.

Introduction: Orexin-containing neurons exist in the lateral hypothalamic region, sending their projections toward mesolimbic regions such as the Ventral Tegmental Area (VTA).

Methods: In the current study, a Reinstatement model is used to examine the effects of intra-VTA administration of SB334867 as an Orexin-1 Receptor (OX1R) antagonist on drug priming- and Forced Swim Stress (FSS)-induced reinstatement of morphine. Eighty-eight male adult albino Wistar rats, weighing 200-280 g, were bilaterally implanted by cannulas into the VTA.

A Central Amygdala-Ventrolateral Periaqueductal Gray Matter Pathway for Pain in a Mouse Model of Depression-like Behavior.

Background: The mechanisms underlying depression-associated pain remain poorly understood. Using a mouse model of depression, the authors hypothesized that the central amygdala-periaqueductal gray circuitry is involved in pathologic nociception associated with depressive states.

Methods: The authors used chronic restraint stress to create a mouse model of nociception with depressive-like behaviors.

A Central Amygdala Input to the Parafascicular Nucleus Controls Comorbid Pain in Depression.

While comorbid pain in depression (CP) occurs at a high rate worldwide, the neural connections underlying the core symptoms of CP have yet to be elucidated. Here, we define a pathway whereby GABAergic neurons from the central nucleus of the amygdala (GABA) project to glutamatergic neurons in the parafascicular nucleus (Glu). These Glu neurons relay directly to neurons in the second somatosensory cortex (S2), a well-known area involved in pain signal processing.

Direct auditory cortical input to the lateral periaqueductal gray controls sound-driven defensive behavior.

Threatening sounds can elicit a series of defensive behavioral reactions in animals for survival, but the underlying neural substrates are not fully understood. Here, we demonstrate a previously unexplored neural pathway in mice that projects directly from the auditory cortex (ACx) to the lateral periaqueductal gray (lPAG) and controls noise-evoked defensive behaviors. Electrophysiological recordings showed that the lPAG could be excited by a loud noise that induced an escape-like behavior.

Involvement of orexinergic receptors in the nucleus accumbens, in the effect of forced swim stress on the reinstatement of morphine seeking behaviors.

Orexinergic system is involved in primary rewards; the neural circuit of the ventral tegmental area (VTA), nucleus accumbens (NAc), prefrontal cortex and amygdala represents overlapping elements mediating the rewarding effects of drugs and stressful experiences. The NAc integrates reward-related information from the VTA. Also, it has been indicated that orexinergic system activates the mesolimbic dopamine projecting neurons to the NAc and promotes the development of reward in rodents.

Antagonism of the D1- and D2-like dopamine receptors in the nucleus accumbens attenuates forced swim stress- and morphine priming-induced reinstatement of extinguished rats.

Dopaminergic pathways from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) play a critical role in reward-related phenomena as well as in the reinstatement of drug-seeking behavior. Stress is a major trigger for inducing reinstatement, however, the interaction between stress and the dopaminergic system is not well known. The present study was undertaken to investigate the effect of D1- and D2-like dopamine receptors within the NAc in forced swim stress (FSS)- and priming-induced reinstatement of morphine-seeking behaviors.

Reversible inactivation of the lateral hypothalamus reversed high reward choices in cost-benefit decision-making in rats.

The Lateral hypothalamus (LH) is an important component of the networks underlying the control of feeding and other motivated behaviors. Cost-benefit decision-making is mediated largely by the prefrontal cortex (PFC) which strongly innervates the LH. Therefore, in the current study, we conducted a series of experiments to elucidate the role of the perifornical area of the lateral hypothalamus (PeF-LH) in effort and/or delay-based decision-making.

Role of intra-accumbal orexin receptors in the acquisition of morphine-induced conditioned place preference in the rats.

Orexin receptor shave essential role in the induction of reward-related behaviors to several drugs of abuse. In the present study, we investigated the effects of bilateral administration of SB334867, as an orexin-1 receptor antagonist, and TCS OX2 29, as an orexin-2 receptor antagonist, into the nucleus accumbens (NAc) on the acquisition of morphine-induced conditioned place preference (CPP) in the rats. Adult male Wistar rats (n=80; 220-250g) were entered in a CPP paradigm.