Delta Opioid Receptor Signaling Promotes Resilience to Stress Under the Repeated Social Defeat Paradigm in Mice.

The adaptation to chronic stress is highly variable across individuals. Resilience to stress is a complex process recruiting various brain regions and neurotransmitter systems. The aim of this study was to investigate the involvement of endogenous opioid enkephalin (ENK) signaling in the development of stress resilience in mice.

Enkephalins: Endogenous Analgesics with an Emerging Role in Stress Resilience.

Psychological stress is a state of mental or emotional strain or tension that results from adverse or demanding circumstances. Chronic stress is well known to induce anxiety disorders and major depression; it is also considered a risk factor for Alzheimer's disease. Stress resilience is a positive outcome that is associated with preserved cognition and healthy aging.

Regional expression and ultrastructural localization of EphA7 in the hippocampus and cerebellum of adult rat.

EphA7 is expressed in the adult central nervous system (CNS), where its roles are yet poorly defined. We mapped its distribution using in situ hybridization (ISH) and immunohistochemistry (IHC) combined with light (LM) and electron microscopy (EM) in adult rat and mouse brain. The strongest ISH signal was in the hippocampal pyramidal and granule cell layers.

EphA4 is Involved in Sleep Regulation but Not in the Electrophysiological Response to Sleep Deprivation.

Study Objectives: Optimal sleep is ensured by the interaction of circadian and homeostatic processes. Although synaptic plasticity seems to contribute to both processes, the specific players involved are not well understood. The EphA4 tyrosine kinase receptor is a cell adhesion protein regulating synaptic plasticity.

Extracellular Na(+) levels regulate formation and activity of the NaX/alpha1-Na(+)/K(+)-ATPase complex in neuronal cells.

MnPO neurons play a critical role in hydromineral homeostasis regulation by acting as sensors of extracellular sodium concentration ([Na(+)]out). The mechanism underlying Na(+)-sensing involves Na(+)-flow through the NaX channel, directly regulated by the Na(+)/K(+)-ATPase α1-isoform which controls Na(+)-influx by modulating channel permeability. Together, these two partners form a complex involved in the regulation of intracellular sodium ([Na(+)]in).

Respiratory manifestations of panic disorder in animals and humans: a unique opportunity to understand how supramedullary structures regulate breathing.

The control of breathing is commonly viewed as being a "brainstem affair". As the topic of this special issue of Respiratory Physiology and Neurobiology indicates, we should consider broadening this notion since the act of breathing is also tightly linked to many functions other than close regulation of arterial blood gases. Accordingly, "non-brainstem" structures can exert a powerful influence on the core elements of the respiratory control network and as it is often the case, the importance of these structures is revealed when their dysfunction leads to disease.

Enkephalin knockdown in the basolateral amygdala reproduces vulnerable anxiety-like responses to chronic unpredictable stress.

The endogenous enkephalins (ENKs) are potential candidates participating in the naturally occurring variations in coping styles and determining the individual capacities for adaptation during chronic stress exposure. Here we demonstrate that there is a large variance in individual behavioral, as well as in physiological outcomes, in a population of Sprague-Dawley rats subjected to 3 weeks of chronic unpredictable stress (CUS). Separation of resilient and vulnerable subpopulations reveals specific long-term neuroadaptation in the ENKergic brain circuits.

Enkephalin downregulation in the nucleus accumbens underlies chronic stress-induced anhedonia.

Restraint and immobilization have been extensively used to study habituation of the neuroendocrine response to a repeated stressor, but behavioral consequences of this stress regimen remain largely uncharacterized. In this study, we used sucrose preference and the elevated-plus maze to probe behavioral alterations resulting from 14 days of restraint in rats. We observed a decrease in sucrose preference in stressed animals, particularly in a subgroup of individuals, but no alteration in anxiety behaviors (as measured in the elevated-plus maze) four days following the last restraint.

Striatal pre-enkephalin overexpression improves Huntington's disease symptoms in the R6/2 mouse model of Huntington's disease.

The reduction of pre-enkephalin (pENK) mRNA expression might be an early sign of striatal neuronal dysfunction in Huntington's disease (HD), due to mutated huntingtin protein. Indeed, striatopallidal (pENK-containing) neurodegeneration occurs at earlier stage of the disease, compare to the loss of striatonigral neurons. However, no data are available about the functional role of striatal pENK in HD.

Multiple episodes of sodium depletion in the rat: a remodeling of the electrical properties of median preoptic nucleus neurons.

In rat brain, the detection and integration of chemosensory and neural signals are achieved, inter alia, by the median preoptic nucleus (MnPO) during a disturbance of the hydromineral balance. This is allowed through the presence of the sodium (Na(+) ) sensor neurons. Interestingly, enkephalins and mu-opioid receptors (μ-ORs) are known for their role in ingestive behaviors and have previously been shown to regulate the excitability of MnPO neurons following a single Na(+) depletion.

Enkephalin and dynorphin mRNA expression are associated with resilience or vulnerability to chronic social defeat stress.

There are important and enduring differences between individuals in the magnitude of all aspects of the stress response. Among the neuropeptide systems, the endogenous opioids enkephalin (ENK) and dynorphin (DYN), are very interesting candidates to participate in the naturally occurring variations in coping styles and to determine the individual capacity for adaptation during chronic stress exposure. Under chronic social stress exposure, we hypothesize that changes in the ENKergic vs DYNergic neuronal systems within specific nuclei of the basal forebrain contribute to naturally occurring variations in coping styles and will determine individual capacities for stress adaptation.

Neonatal stress augments the hypoxic chemoreflex of adult male rats by increasing AMPA receptor-mediated modulation.

Neonatal stress disrupts the developmental trajectory of homeostatic systems. Adult (8- to 10-week-old) male rats exposed to maternal separation (a form of neonatal stress) display several traits reported in patients suffering from sleep-disordered breathing, including an augmented hypoxic chemoreflex. To understand the mechanisms behind this effect, we tested the hypothesis that neonatal stress augments glutamatergic neurotransmission in three regions involved in respiratory regulation, namely the nucleus of the solitary tract, the paraventricular nucleus of the hypothalamus and the phrenic motor nucleus.

Regulation of central Na+ detection requires the cooperative action of the NaX channel and α1 Isoform of Na+/K+-ATPase in the Na+-sensor neuronal population.

The median preoptic nucleus (MnPO) holds a strategic position in the hypothalamus. It is adjacent to the third ventricle; hence, it can directly access the ionic composition of the CSF. MnPO neurons play a critical role in hydromineral homeostasis regulation by acting as central sensors of extracellular Na(+) concentration ([Na(+)](ext)).

Enkephalin knockdown in the central amygdala nucleus reduces unconditioned fear and anxiety.

The endogenous opioid enkephalins (ENK) are highly expressed in the central nucleus of the amygdaloid complex (CeA) where several lines of evidence point to a potential role in the modulation of fear and anxiety. In this study, we aimed to assess the role of CeA ENK using local injections of a lentiviral vector expressing a short hairpin RNA (shRNA) targeting ENK in Sprague-Dawley rats. We injected this vector in the CeA and a 56% downregulation of ENK mRNA was observed in animals when compared with scrambled shRNA animals.

Intrinsic properties of the sodium sensor neurons in the rat median preoptic nucleus.

The essential role of the median preoptic nucleus (MnPO) in the integration of chemosensory information associated with the hydromineral state of the rat relies on the presence of a unique population of sodium (Na+) sensor neurons. Little is known about the intrinsic properties of these neurons; therefore, we used whole cell recordings in acute brain slices to determine the electrical fingerprints of this specific neural population of rat MnPO. The data collected from a large sample of neurons (115) indicated that the Na+ sensor neurons represent a majority of the MnPO neurons in situ (83%).

The Expression Pattern of the Na(+) Sensor, Na(X) in the Hydromineral Homeostatic Network: A Comparative Study between the Rat and Mouse.

The Scn7a gene encodes for the specific sodium channel Na(X), which is considered a primary determinant of sodium sensing in the brain. Only partial data exist describing the Na(X) distribution pattern and the cell types that express Na(X) in both the rat and mouse brain. To generate a global view of the sodium detection mechanisms in the two rodent brains, we combined Na(X) immunofluorescence with fluorescent cell markers to map and identify the Na(X)-expressing cell populations throughout the network involved in hydromineral homeostasis.

Increased anxiety-like behaviors in rats experiencing chronic inflammatory pain.

For many patients, chronic pain is often accompanied, and sometimes amplified, by co-morbidities such as anxiety and depression. Although it represents important challenges, the establishment of appropriate preclinical behavioral models contributes to drug development for treating chronic inflammatory pain and associated psychopathologies. In this study, we investigated whether rats experiencing persistent inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA) developed anxiety-like behaviors, and whether clinically used analgesic and anxiolytic drugs were able to reverse CFA-induced anxiety-related phenotypes.

Neuroanatomical characterization of endogenous opioids in the bed nucleus of the stria terminalis.

Numerous neuroanatomical data indicate that the bed nucleus of the stria terminalis (BST) provides an interface between cortical and amygdaloid neurons, and effector neurons modulating motor, autonomic and neuroendocrine responses. Distinct divisions of the BST may be involved in stress response, homeostatic regulation, nociception, and motivated behaviors. Endogenous opioid peptides and receptors are expressed in the BST, but their exact distribution is poorly characterized.

Postsynaptic mu-opioid receptor response in the median preoptic nucleus is altered by a systemic sodium challenge in rats.

The median preoptic nucleus (MnPO) is an integrator site for the chemosensory and neural signals induced by a perturbation in the hydromineral balance, and it is highly involved in controlling fluid and electrolyte ingestion. Here, we hypothesize that opioid peptides, previously recognized to control ingestive behaviors, may regulate the excitability of MnPO neurons and that this regulatory action may depend on the natriuric (Na(+)) status of body fluid compartments. Our results show that activation of mu-, but not delta-, opioid receptors (OR) triggered a membrane hyperpolarization by recruiting a G-protein-regulated inward-rectifier K(+) (GIRK) conductance in 41% of the neurons tested.

Neonatal maternal separation and enhancement of the inspiratory (phrenic) response to hypoxia in adult rats: disruption of GABAergic neurotransmission in the nucleus tractus solitarius.

Neonatal maternal separation (NMS) alters respiratory control development. Adult male rats previously subjected to NMS show a hypoxic ventilatory response 25% greater than controls. During hypoxia, gamma-aminobutyric acid (GABA) release within the nucleus tractus solitarius (NTS) modulates the magnitude of the ventilatory response.

Enkephalin co-expression with classic neurotransmitters in the amygdaloid complex of the rat.

This study aimed at characterizing the neurotransmitter phenotype of enkephalin neurons in the rat amygdaloid complex. We first established the detailed distribution of vesicular glutamate transporters 1 and 2 (VGLUT1 and -2) and glutamate decarboxylase 65 (GAD65) in the amygdala by using in situ hybridization. In the amygdaloid complex, GAD65 is strongly expressed in striatal-like divisions, namely, the anterior amygdaloid area, the central nucleus (CEA), the intercalated nuclei, and the dorsal part of the medial nucleus (MEA).

Neonatal maternal separation and enhancement of the hypoxic ventilatory response in rat: the role of GABAergic modulation within the paraventricular nucleus of the hypothalamus.

Neonatal maternal separation (NMS) affects respiratory control development as adult male (but not female) rats previously subjected to NMS show a hypoxic ventilatory response 25% greater than controls. The paraventricular nucleus of the hypothalamus (PVN) is an important modulator of respiratory activity. In the present study, we hypothesized that in awake rats, altered GABAergic inhibition within the PVN contributes to the enhancement of hypoxic ventilatory response observed in rats previously subjected to NMS.

Challenged sodium balance and expression of angiotensin type 1A receptor mRNA in the hypothalamus of Wistar and Dahl rat strains.

The present study investigates the influence of a chronic high Na+ diet (8% Na+) on the expression of the angiotensin type 1A (AT1A) receptor gene in the lamina terminalis and paraventricular nucleus of the hypothalamus (PVH) in normotensive Wistar (W) rats, as well as in Dahl salt-resistant (DR) and Dahl salt-sensitive (DS) rats. Three weeks of 8% Na+ diet led to a higher blood pressure in DS rats compared to DR and W rats. Moreover, the high Na+ diet was correlated with a decreased expression of AT1A receptor mRNA in the median preoptic nucleus (MnPO) and in the PVH of DS rats, compared to DR and W rats.

Neonatal maternal separation induces sex-specific augmentation of the hypercapnic ventilatory response in awake rat.

Neonatal maternal separation (NMS) is a form of stress that exerts persistent, sex-specific effects on the hypoxic ventilatory response. Adult male rats previously subjected to NMS show a 25% increase in the response, whereas NMS females show a response 30% lower than controls (8). To assess the extent to which NMS affects ventilatory control development, we tested the hypothesis that NMS alters the ventilatory response to hypercapnia in awake, unrestrained rats.

Enkephalinergic afferents of the centromedial amygdala in the rat.

The connectivity of the amygdaloid complex has been extensively explored with both anterograde and retrograde tracers. Even though the afferents of the centromedial amygdala [comprising the central (CEA) and medial (MEA) amygdaloid nuclei] are well established, relatively little is known about the neuropeptide phenotype of these connections. In this study, we first examined the distribution of mu-opioid receptor (MOR) and delta-opioid receptor (DOR) in the amygdala via in situ hybridization and immunohistochemistry.