Hypothalamic CRF neurons facilitate brain reward function.

Aversive stimuli activate corticotropin-releasing factor (CRF)-expressing neurons in the paraventricular nucleus of hypothalamus (PVNCRF neurons) and other brain stress systems to facilitate avoidance behaviors. Appetitive stimuli also engage the brain stress systems, but their contributions to reward-related behaviors are less well understood. Here, we show that mice work vigorously to optically activate PVNCRF neurons in an operant chamber, indicating a reinforcing nature of these neurons. The reinforcing property of these neurons is not mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis. We found that PVNCRF neurons send direct projections to the ventral tegmental area (VTA), and selective activation of these projections induced robust self-stimulation behaviors, without activation of the HPA axis. Similar to the PVNCRF cell bodies, self-stimulation of PVNCRF-VTA projection was dramatically attenuated by systemic pretreatment of CRF receptor 1 or dopamine D1 receptor (D1R) antagonist and augmented by corticosterone synthesis inhibitor metyrapone, but not altered by dopamine D2 receptor (D2R) antagonist. Furthermore, we found that activation of PVNCRF-VTA projections increased c-Fos expression in the VTA dopamine neurons and rapidly triggered dopamine release in the nucleus accumbens (NAc), and microinfusion of D1R or D2R antagonist into the NAc decreased the self-stimulation of these projections. Together, our findings reveal an unappreciated role of PVNCRF neurons and their VTA projections in driving reward-related behaviors, independent of their core neuroendocrine functions. As activation of PVNCRF neurons is the final common path for many stress systems, our study suggests a novel mechanism underlying the positive reinforcing effect of stressful stimuli.

LPA1 receptors in the lateral habenula regulate negative affective states associated with alcohol withdrawal.

The role of lysophosphatidic acid (LPA) signaling in psychiatric disorders and drug abuse is significant. LPA receptors are widely expressed in the central nervous system, including the lateral habenula (LHb). Recent studies suggest that LHb is involved in a negative emotional state during alcohol withdrawal, which can lead to relapse. The current study examines the role of LHb LPA signaling in the negative affective state associated with alcohol withdrawal. Adult male Long-Evans rats were trained to consume either alcohol or water for eight weeks. At 48 h of withdrawal, alcohol-drinking rats showed anxiety- and depression-like symptoms, along with a significant increase in LPA signaling and related neuronal activation molecules, including autotaxin (ATX, Enpp2), LPA receptor 1/3 (LPA1/3), ßCaMKII, and c-Fos. However, there was a decrease in lipid phosphate phosphatase-related protein type 4 (LPPR4) in the LHb. Intra-LHb infusion of the LPA1/3 receptor antagonist ki-16425 or PKC-γ inhibitor Go-6983 reduced the abnormal behaviors and elevated relapse-like ethanol drinking. It also normalized high LPA1/3 receptors and enhanced AMPA GluA1 phosphorylation in Ser831 and GluA1/GluA2 ratio. Conversely, selective activation of LPA1/3 receptors by intra-LHb infusion of 18:1 LPA induced negative affective states and upregulated ßCaMKII-AMPA receptor phosphorylation in Naive rats, which were reversed by pretreatment with intra-LHb Go-6983. Our findings suggest that disturbances in LPA signaling contribute to adverse affective disorders during alcohol withdrawal, likely through PKC-γ/ßCaMKII-linked glutamate signaling. Targeting LPA may therefore be beneficial for individuals suffering from alcohol use disorders.

Corticospinal circuit neuroplasticity may involve silent synapses: Implications for functional recovery facilitated by neuromodulation after spinal cord injury.

Spinal cord injury (SCI) leads to devastating physical consequences, such as severe sensorimotor dysfunction even lifetime disability, by damaging the corticospinal system. The conventional opinion that SCI is intractable due to the poor regeneration of neurons in the adult central nervous system (CNS) needs to be revisited as the CNS is capable of considerable plasticity, which underlie recovery from neural injury. Substantial spontaneous neuroplasticity has been demonstrated in the corticospinal motor circuitry following SCI. Some of these plastic changes appear to be beneficial while others are detrimental toward locomotor function recovery after SCI. The beneficial corticospinal plasticity in the spared corticospinal circuits can be harnessed therapeutically by multiple contemporary neuromodulatory approaches, especially the electrical stimulation-based modalities, in an activity-dependent manner to improve functional outcomes in post-SCI rehabilitation. Silent synapse generation and unsilencing contribute to profound neuroplasticity that is implicated in a variety of neurological disorders, thus they may be involved in the corticospinal motor circuit neuroplasticity following SCI. Exploring the underlying mechanisms of silent synapse-mediated neuroplasticity in the corticospinal motor circuitry that may be exploited by neuromodulation will inform a novel direction for optimizing therapeutic repair strategies and rehabilitative interventions in SCI patients.

Comorbidity of Post-Traumatic Stress Disorder and Alcohol Use Disorder: Animal Models and Associated Neurocircuitry.

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are prevalent neuropsychiatric disorders and frequently co-occur concomitantly. Individuals suffering from this dual diagnosis often exhibit increased symptom severity and poorer treatment outcomes than those with only one of these diseases. Lacking standard preclinical models limited the exploration of neurobiological mechanisms underlying PTSD and AUD comorbidity. In this review, we summarize well-accepted preclinical model paradigms and criteria for developing successful models of comorbidity. We also outline how PTSD and AUD affect each other bidirectionally in the nervous nuclei have been heatedly discussed recently. We hope to provide potential recommendations for future research.

Spinal cord representation of motor cortex plasticity reflects corticospinal tract LTP.

Although it is well known that activity-dependent motor cortex (MCX) plasticity produces long-term potentiation (LTP) of local cortical circuits, leading to enhanced muscle function, the effects on the corticospinal projection to spinal neurons has not yet been thoroughly studied. Here, we investigate a spinal locus for corticospinal tract (CST) plasticity in anesthetized rats using multichannel recording of motor-evoked, intraspinal local field potentials (LFPs) at the sixth cervical spinal cord segment. We produced LTP by intermittent theta burst electrical stimulation (iTBS) of the wrist area of MCX. Approximately 3 min of MCX iTBS potentiated the monosynaptic excitatory LFP recorded within the CST termination field in the dorsal horn and intermediate zone for at least 15 min after stimulation. Ventrolaterally, in the spinal cord gray matter, which is outside the CST termination field in rats, iTBS potentiated an oligosynaptic negative LFP that was localized to the wrist muscle motor pool. Spinal LTP remained robust, despite pharmacological blockade of iTBS-induced LTP within MCX using MK801, showing that activity-dependent spinal plasticity can be induced without concurrent MCX LTP. Pyramidal tract iTBS, which preferentially activates the CST, also produced significant spinal LTP, indicating the capacity for plasticity at the CST-spinal interneuron synapse. Our findings show CST monosynaptic LTP in spinal interneurons and demonstrate that spinal premotor circuits are capable of further modifying descending MCX control signals in an activity-dependent manner.

Chronic Nicotine Alters Corticostriatal Plasticity in the Striatopallidal Pathway Mediated By NR2B-Containing Silent Synapses.

Smoking is the leading cause of preventable death in the United States and success rates for quitting remain low. High relapse rates are attributed to pervasive nicotine-reinforced associative learning of incentive cues that is highly resistant to extinction. Why such learning is so persistent is poorly understood but may arise as a consequence of neuroadaptations in synaptic plasticity induced by chronic nicotine. We used whole-cell patch clamp recording to investigate the effect of chronic nicotine (cNIC) on synaptic plasticity in dopamine D2 receptor-expressing medium-spiny neurons in the indirect, striatopallidal pathway in dorsolateral striatum. Mice exposed to cNIC exhibited long-term potentiation in response to high-frequency stimulation instead of the expected depression. cNIC decreased baseline AMPA/NMDA ratio, arising from increased NMDA currents enriched in the NR2B subunit with a concomitant upregulation of NMDA-only, silent synapses. These data demonstrate that cNIC can increase silent synapses in MSNs, as observed with cocaine and opiates, and alter the regulation of corticostriatal plasticity. Prior work has characterized cocaine- and morphine-induced upregulation of silent synapses in the ventral striatum; we show it can occur in the dorsal striatum, a region associated with later stages of addiction, craving, and cue-induced relapse.

Target of HIV-1 Envelope Glycoprotein gp120-Induced Hippocampal Neuron Damage: Role of Voltage-Gated K(+) Channel Kv2.1.

Human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein 120 (gp120) has been reported to be toxic to the hippocampal neurons, and to be involved in the pathogenesis of HIV-1-associated neurocognitive disorders (HAND). Accumulating evidence has demonstrated that voltage-gated potassium (Kv) channels, especially the outward delayed-rectifier K(+) (Ik) channels, play a critical role in gp120-induced cortical neuronal death in vitro. However, the potential mechanisms underlying the hippocampal neuronal injury resulted from gp120-mediated neurotoxicity remain poorly understood. Using whole-cell patch clamp recording in cultured hippocampal neurons, this study found that gp120 significantly increased the outward delayed-rectifier K(+) currents (Ik). Meanwhile, Western blot assay revealed that gp120 markedly upregulated Kv2.1 protein levels, which was consistent with the increased Ik density. With Western blot and terminal deoxynucleotidyl transferase dUTP nick end labeling assays, it was discovered that gp120-induced neuronal injury was largely due to activation of Kv2.1 channels and resultant apoptosis mediated by caspase-3 activation, as the pharmacological blockade of Kv2.1 channels largely attenuated gp120-induced cell damage and caspase-3 expression. Moreover, p38 MAPK was demonstrated to participate in gp120-induced hippocampal neural damage, since p38 MAPK antagonist (SB203580) partially abrogated gp120-induced Kv2.1 upregulation and neural apoptosis. Taken together, these results suggest that gp120 induces hippocampal neuron apoptosis by enhancement of the Ik, which might be associated with increased Kv2.1 expression via the p38 MAPK pathway.

Neuropathogenesis of HIV-1-associated neurocognitive disorders: a possible involvement of D-serine.

A unique feature of N-methyl-D-aspartate receptors (NMDARs) that distinguishes them from other ionic receptors is that their activation requires more than one agonist to bind simultaneously to distinct binding sites on the receptor. D-serine, a co-agonist binding to the glycine site of NMDARs, has been implicated in several NMDAR-dependent physiological processes, and altered D-serine levels under certain pathophysiological conditions contribute to neural dysfunction via NMDARs in the central nervous system. Entry of HIV-1 in the brain causes neuronal injury leading to cognitive, behavioral and motor impairments known as HIV-associated neurocognitive disorders (HAND). As HIV-1 does not infect neurons, neuronal injury is believed to be primarily mediated by an indirect mechanism,that is, HIV-1-infected and/or immune-activated macrophages and microglial cells release soluble molecules leading to neuronal injury or death. Among the soluble factors is D-serine. In this article we try to address recent progresses on the role D-serine might play in the pathogenesis of neurodegenerative disorders with a particular emphasis of the involvement of D-serine in HIV-1-associated neurotoxicity.

Enhancement of NMDA receptor-mediated excitatory postsynaptic currents by gp120-treated macrophages: implications for HIV-1-associated neuropathology.

A plethora of prior studies has linked HIV-1-infected and immune activated brain mononuclear phagocytes (MP; blood borne macrophages and microglia) to neuronal dysfunction. These are modulated by N-methyl-D-aspartate receptor (NMDAR) antagonists and supporting their relevance for HIV-1-associated nervous system disease. The role of NMDAR subsets in HIV-1-induced neuronal injury, nonetheless, is poorly understood. To this end, we investigated conditioned media from HIV-1gp120-treated human monocyte-derived-macrophages (MDM) for its abilities to affect NMDAR-mediated excitatory postsynaptic currents (EPSC(NMDAR)) in rat hippocampal slices. Bath application of gp120-treated MDM-conditioned media (MCM) produced an increase of EPSC(NMDAR). In contrast, control (untreated) MCM had limited effects on EPSC(NMDAR). Testing NR2A NMDAR (NR2AR)-mediated EPSC (EPSC(NR2AR)) and NR2B NMDAR (NR2BR)-mediated EPSC (EPSC(NR2BR)) for MCM showed significant increased EPSC(NR2BR) when compared to EPSC(NR2AR) enhancement. When synaptic NR2AR-mediated EPSC was blocked by bath application of MK801 combined with low frequency stimulations, MCM retained its ability to enhance EPSC(NMDAR) evoked by stronger stimulations. This suggested that increase in EPSC(NMDAR) was mediated, in part, through extra-synaptic NR2BR. Further analyses revealed that the soluble factors with low (<3 kD) to medium (3-10 kD) molecular weight mediated the observed increases in EPSC(NMDAR). The link between activation of NR2BRs and HIV-1gp120 MCM for neuronal injury was demonstrated by NR2BR but not NR2AR blockers. Taken together, these results indicate that macrophage secretory products induce neuronal injury through extra-synaptic NR2BRs.