Ventromedial hypothalamic nucleus subset stimulates tissue thermogenesis via preoptic area outputs.

Objective: Hypothalamic signals potently stimulate energy expenditure by engaging peripheral mechanisms to restore energy homeostasis. Previous studies have identified several critical hypothalamic sites (e.g.

Targeting Prefrontal Cortex Dysfunction in Pain.

The prefrontal cortex (PFC) has justifiably become a significant focus of chronic pain research. Collectively, decades of rodent and human research have provided strong rationale for studying the dysfunction of the PFC as a contributing factor in the development and persistence of chronic pain and as a key supraspinal mechanism for pain-induced comorbidities such as anxiety, depression, and cognitive decline. Chronic pain alters the structure, chemistry, and connectivity of PFC in both humans and rodents.

Converging Effects of Chronic Pain and Binge Alcohol Consumption on Anterior Insular Cortex Neurons Projecting to the Dorsolateral Striatum in Male Mice.

Chronic pain and alcohol use disorder (AUD) are highly comorbid, and patients with chronic pain are more likely to meet the criteria for AUD. Evidence suggests that both conditions alter similar brain pathways, yet this relationship remains poorly understood. Prior work shows that the anterior insular cortex (AIC) is involved in both chronic pain and AUD.

Mouse models of surgical and neuropathic pain produce distinct functional alterations to prodynorphin expressing neurons in the prelimbic cortex.

The medial prefrontal cortex (mPFC) consists of a heterogeneous population of neurons that respond to painful stimuli, and our understanding of how different pain models alter these specific mPFC cell types remains incomplete. A distinct subpopulation of mPFC neurons express prodynorphin (Pdyn), the endogenous peptide agonist for kappa opioid receptors (KORs). Here, we used whole cell patch clamp for studying excitability changes to Pdyn expressing neurons in the prelimbic region of the mPFC (PL neurons) in mouse models of surgical and neuropathic pain.

Topographic organization underlies intrinsic and morphological heterogeneity of central amygdala neurons expressing corticotropin-releasing hormone.

The central nucleus of the amygdala (CeA) network consists of a heterogeneous population of inhibitory GABAergic neurons distributed across distinct subregions. While the specific roles for molecularly defined CeA neurons have been extensively studied, our understanding of functional heterogeneity within classes of molecularly distinct CeA neurons remains incomplete. In addition, manipulation of genetically defined CeA neurons has produced inconsistent behavioral results potentially due to broad targeting across CeA subregions.

Sphingosine-1-phosphate receptor 1 agonist SEW2871 alters membrane properties of late-firing somatostatin expressing neurons in the central lateral amygdala.

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediates a wide spectrum of biological processes including apoptosis, immune response and inflammation. Here, we sought to understand how S1P signaling affects neuronal excitability in the central amygdala (CeA), which is a brain region associated with fear learning, aversive memory, and the affective dimension of pain. Because the G-protein coupled S1P receptor 1 (S1PR) has been shown to be the primary mediator of S1P signaling, we utilized S1PR agonist SEW2871 and S1PR antagonist NIBR to determine a potential role of S1PR in altering the cellular physiology of neurons in the lateral division of the CeA (CeL) that share the neuronal lineage marker somatostatin (Sst).

Prenatal methadone exposure disrupts behavioral development and alters motor neuron intrinsic properties and local circuitry.

Despite the rising prevalence of methadone treatment in pregnant women with opioid use disorder, the effects of methadone on neurobehavioral development remain unclear. We developed a translational mouse model of prenatal methadone exposure (PME) that resembles the typical pattern of opioid use by pregnant women who first use oxycodone then switch to methadone maintenance pharmacotherapy, and subsequently become pregnant while maintained on methadone. We investigated the effects of PME on physical development, sensorimotor behavior, and motor neuron properties using a multidisciplinary approach of physical, biochemical, and behavioral assessments along with brain slice electrophysiology and in vivo magnetic resonance imaging.

Peripheral nerve injury reduces the excitation-inhibition balance of basolateral amygdala inputs to prelimbic pyramidal neurons projecting to the periaqueductal gray.

Cellular and synaptic mechanisms underlying how chronic pain induces maladaptive alterations to local circuits in the medial prefrontal cortex (mPFC), while emerging, remain unresolved. Consistent evidence shows that chronic pain attenuates activity in the prelimbic (PL) cortex, a mPFC subregion. This reduced activity is thought to be driven by increased inhibitory tone within PL circuits.

Sex-Specific Disruption of Distinct mPFC Inhibitory Neurons in Spared-Nerve Injury Model of Neuropathic Pain.

The medial prefrontal cortex (mPFC) modulates a range of behaviors, including responses to noxious stimuli. While various pain modalities alter mPFC function, our understanding of changes to specific cell types underlying pain-induced mPFC dysfunction remains incomplete. Proper activity of cortical GABAergic interneurons is essential for normal circuit function.

The Electrophysiological Determinants of Corticospinal Motor Neuron Vulnerability in ALS.

The brain is complex and heterogeneous. Even though numerous independent studies indicate cortical hyperexcitability as a potential contributor to amyotrophic lateral sclerosis (ALS) pathology, the mechanisms that are responsible for upper motor neuron (UMN) vulnerability remain elusive. To reveal the electrophysiological determinants of corticospinal motor neuron (CSMN, a.

Gpr17 deficiency in POMC neurons ameliorates the metabolic derangements caused by long-term high-fat diet feeding.

Background: Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) control energy homeostasis by sensing hormonal and nutrient cues and activating secondary melanocortin sensing neurons. We identified the expression of a G protein-coupled receptor, Gpr17, in the ARH and hypothesized that it contributes to the regulatory function of POMC neurons on metabolism.

Methods: In order to test this hypothesis, we generated POMC neuron-specific Gpr17 knockout (PGKO) mice and determined their energy and glucose metabolic phenotypes on normal chow diet (NCD) and high-fat diet (HFD).

Spared nerve injury differentially alters parabrachial monosynaptic excitatory inputs to molecularly specific neurons in distinct subregions of the central amygdala.

Dissecting the organization of circuit pathways involved in pain affect is pivotal for understanding behavior associated with noxious sensory inputs. The central nucleus of the amygdala (CeA) comprises distinct populations of inhibitory GABAergic neurons expressing a wide range of molecular markers. CeA circuits are associated with aversive learning and nociceptive responses.

The central amygdala to periaqueductal gray pathway comprises intrinsically distinct neurons differentially affected in a model of inflammatory pain.

Key Points: The central nucleus of the amygdala (CeA) encompasses the main output pathways of the amygdala, a temporal lobe structure essential in affective and cognitive dimensions of pain. A major population of neurons in the CeA send projections to the periaqueductal gray (PAG), a key midbrain structure that mediates coping strategies in response to threat or stress. CeA-PAG neurons are topographically organized based on their targeted subregion within the PAG.

Altered Excitability and Local Connectivity of mPFC-PAG Neurons in a Mouse Model of Neuropathic Pain.

The medial prefrontal cortex (mPFC) plays a major role in both sensory and affective aspects of pain. There is extensive evidence that chronic pain produces functional changes within the mPFC. However, our understanding of local circuit changes to defined subpopulations of mPFC neurons in chronic pain models remains unclear.

Specific Targeting of the Basolateral Amygdala to Projectionally Defined Pyramidal Neurons in Prelimbic and Infralimbic Cortex.

Adjacent prelimbic (PL) and infralimbic (IL) regions in the medial prefrontal cortex have distinct roles in emotional learning. A complete mechanistic understanding underlying this dichotomy remains unclear. Here we explored targeting of specific PL and IL neurons by the basolateral amygdala (BLA), a limbic structure pivotal in pain and fear processing.

Highly differentiated cellular and circuit properties of infralimbic pyramidal neurons projecting to the periaqueductal gray and amygdala.

The infralimbic (IL) cortex is a key node in an inter-connected network involved in fear and emotion processing. The cellular and circuit-level mechanisms whereby IL neurons receive, filter, and modulate incoming signals they project onward to diverse downstream nodes in this complex network remain poorly understood. Using the mouse as our model, we applied anatomical labeling strategies, brain slice electrophysiology, and focal activation of caged glutamate via laser scanning photostimulation (glu-LSPS) for quantitative neurophysiological analysis of projectionally defined neurons in IL.

Systemic platelet dysfunction is the result of local dysregulated coagulation and platelet activation in the brain in a rat model of isolated traumatic brain injury.

Coagulopathy after severe traumatic brain injury (TBI) has been extensively reported. Clinical studies have identified a strong relationship between diminished platelet-rich thrombus formation, responsiveness to adenosine diphosphate agonism, and severity of TBI. The mechanisms that lead to platelet dysfunction in the acute response to TBI are poorly understood.

Probing NMDA receptor GluN2A and GluN2B subunit expression and distribution in cortical neurons.

The spatial distribution of N-methyl-d-aspartate receptor (NMDAR) subunits in layer 5 (L5) neurons of the medial prefrontal cortex (mPFC) is important for integrating input-output signals involved in cognitive functions and motor behavior. In this study, focal laser scanning photostimulation of caged glutamate, slice electrophysiology, and small peptide pharmacology, were used to map the distribution of functional GluN2A and GluN2B subunits of the NMDAR from L5 neurons of wild-type (WT) and GluN2A(-/-) mice. Focal uncaging of glutamate evoked spatially-restricted glutamatergic responses on various dendritic locations of pyramidal neurons in the mPFC.

eGFP expression under UCHL1 promoter genetically labels corticospinal motor neurons and a subpopulation of degeneration-resistant spinal motor neurons in an ALS mouse model.

Understanding mechanisms that lead to selective motor neuron degeneration requires visualization and cellular identification of vulnerable neurons. Here we report generation and characterization of UCHL1-eGFP and hSOD1(G93A)-UeGFP mice, novel reporter lines for cortical and spinal motor neurons. Corticospinal motor neurons (CSMN) and a subset of spinal motor neurons (SMN) are genetically labeled in UCHL1-eGFP mice, which express eGFP under the UCHL1 promoter.

Delayed calcium dysregulation in neurons requires both the NMDA receptor and the reverse Na+/Ca2+ exchanger.

Glutamate-induced delayed calcium dysregulation (DCD) is a causal factor leading to neuronal death. The mechanism of DCD is not clear but Ca2+ influx via N-methyl-d-aspartate receptors (NMDAR) and/or the reverse plasmalemmal Na+/Ca2+ exchanger (NCXrev) could be involved in DCD. However, the extent to which NMDAR and NCX(rev) contribute to glutamate-induced DCD is uncertain.

Corticospinal-specific HCN expression in mouse motor cortex: I(h)-dependent synaptic integration as a candidate microcircuit mechanism involved in motor control.

Motor cortex is a key brain center involved in motor control in rodents and other mammals, but specific intracortical mechanisms at the microcircuit level are largely unknown. Neuronal expression of hyperpolarization-activated current (I(h)) is cell class specific throughout the nervous system, but in neocortex, where pyramidal neurons are classified in various ways, a systematic pattern of expression has not been identified. We tested whether I(h) is differentially expressed among projection classes of pyramidal neurons in mouse motor cortex.

Lidocaine reduces the transition to slow inactivation in Na(v)1.7 voltage-gated sodium channels.

Background And Purpose: The primary use of local anaesthetics is to prevent or relieve pain by reversibly preventing action potential propagation through the inhibition of voltage-gated sodium channels. The tetrodotoxin-sensitive voltage-gated sodium channel subtype Na(v)1.7, abundantly expressed in pain-sensing neurons, plays a crucial role in perception and transmission of painful stimuli and in inherited chronic pain syndromes.

KB-R7943, an inhibitor of the reverse Na+ /Ca2+ exchanger, blocks N-methyl-D-aspartate receptor and inhibits mitochondrial complex I.

Background And Purpose: An isothiourea derivative (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methane sulfonate (KB-R7943), a widely used inhibitor of the reverse Na(+) /Ca(2+) exchanger (NCX(rev)), was instrumental in establishing the role of NCX(rev) in glutamate-induced Ca(2+) deregulation in neurons. Here, the effects of KB-R7943 on N-methyl-D-aspartate (NMDA) receptors and mitochondrial complex I were tested.

Experimental Approach: Fluorescence microscopy, electrophysiological patch-clamp techniques and cellular respirometry with Seahorse XF24 analyzer were used with cultured hippocampal neurons; membrane potential imaging, respirometry and Ca(2+) flux measurements were made in isolated rat brain mitochondria.

Sublayer-specific microcircuits of corticospinal and corticostriatal neurons in motor cortex.

The mammalian motor system is organized around distinct subcortical subsystems, suggesting that the intracortical circuits immediately upstream of spinal cord and basal ganglia might be functionally differentiated as well. We found that the main excitatory pathway in mouse motor cortex, layer 2/3-->5, is fractionated into distinct pathways targeting corticospinal and corticostriatal neurons, which are involved in motor control. However, connections were selective for neurons in certain sublayers: corticospinal neurons in upper layer 5B and corticostriatal neurons in lower 5A.