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Frontiers in Neuroscience 2021Research over the last 20 years regarding the link between circadian rhythms and chronic pain pathology has suggested interconnected mechanisms that are not fully... (Review)
Review
Research over the last 20 years regarding the link between circadian rhythms and chronic pain pathology has suggested interconnected mechanisms that are not fully understood. Strong evidence for a bidirectional relationship between circadian function and pain has been revealed through inflammatory and immune studies as well as neuropathic ones. However, one limitation of many of these studies is a focus on only a few molecules or cell types, often within only one region of the brain or spinal cord, rather than systems-level interactions. To address this, our review will examine the circadian system as a whole, from the intracellular genetic machinery that controls its timing mechanism to its input and output circuits, and how chronic pain, whether inflammatory or neuropathic, may mediate or be driven by changes in these processes. We will investigate how rhythms of circadian clock gene expression and behavior, immune cells, cytokines, chemokines, intracellular signaling, and glial cells affect and are affected by chronic pain in animal models and human pathologies. We will also discuss key areas in both circadian rhythms and chronic pain that are sexually dimorphic. Understanding the overlapping mechanisms and complex interplay between pain and circadian mediators, the various nuclei they affect, and how they differ between sexes, will be crucial to move forward in developing treatments for chronic pain and for determining how and when they will achieve their maximum efficacy.
PubMed: 34276301
DOI: 10.3389/fnins.2021.705173 -
Frontiers in Psychiatry 2023In humans and animals, exposure to changes in internal or external environments causes acute stress, which changes sleep and enhances neurochemical, neuroendocrine, and...
In humans and animals, exposure to changes in internal or external environments causes acute stress, which changes sleep and enhances neurochemical, neuroendocrine, and sympathetic activities. Repeated stress responses play an essential role in the pathogenesis of psychiatric diseases and sleep disorders. However, the underlying mechanism of sleep changes and anxiety disorders in response to acute stress is not well established. In the current study, the effects of restraint stress (RS) on anxiety and sleep-wake cycles in mice were investigated. We found that after RS, the mice showed anxiety-like behavior after RS manipulation and increased the amounts of both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep in the dark period. The increase in sleep time was mainly due to the increased number of episodes of NREM and REM sleep during the dark period. In addition, the mice showed an elevation of the EEG power spectrum of both NREM and REM sleep 2 h after RS manipulation. There was a significant reduction in the EEG power spectrum of both NREM and REM sleep during the darkperiod in the RS condition. The expression of the c-Fos protein was significantly increased in the parabrachial nucleus, bed nucleus of the stria terminalis, central amygdala, and paraventricular hypothalamus by RS manipulation. Altogether, the findings from the present study indicated that neural circuits from the parabrachial nucleus might regulate anxiety and sleep responses to acute stress, and suggest a potential therapeutic target for RS induced anxiety and sleep alterations.
PubMed: 37124267
DOI: 10.3389/fpsyt.2023.1090420 -
Experimental Neurology Nov 2021We examined cell type-specific expression and distribution of rat brain angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, in the rodent brain. ACE2 is...
We examined cell type-specific expression and distribution of rat brain angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, in the rodent brain. ACE2 is ubiquitously present in brain vasculature, with the highest density of ACE2 expressing capillaries found in the olfactory bulb, the hypothalamic paraventricular, supraoptic, and mammillary nuclei, the midbrain substantia nigra and ventral tegmental area, and the hindbrain pontine nucleus, the pre-Bötzinger complex, and nucleus of tractus solitarius. ACE2 was expressed in astrocytes and astrocytic foot processes, pericytes and endothelial cells, key components of the blood-brain barrier. We found discrete neuronal groups immunopositive for ACE2 in brainstem respiratory rhythm generating centers, including the pontine nucleus, the parafascicular/retrotrapezoid nucleus, the parabrachial nucleus, the Bötzinger, and pre-Bötzinger complexes and the nucleus of tractus solitarius; in the arousal-related pontine reticular nucleus and gigantocellular reticular nuclei; in brainstem aminergic nuclei, including substantia nigra, ventral tegmental area, dorsal raphe, and locus coeruleus; in the epithalamic habenula, hypothalamic paraventricular and supramammillary nuclei; and in the hippocampus. Identification of ACE2-expressing neurons in rat brain within well-established functional circuits facilitates prediction of possible neurological manifestations of brain ACE2 dysregulation during and after COVID-19 infection.
Topics: Angiotensin-Converting Enzyme 2; Animals; Brain; COVID-19; Central Nervous System Diseases; Male; Rats; Rats, Wistar; SARS-CoV-2
PubMed: 34400158
DOI: 10.1016/j.expneurol.2021.113837 -
Neuron Dec 2018Response to danger needs to be rapid and appropriate. In humans, nocifensive behaviors often precede conscious pain perception. Much is known about local spinal cord...
Response to danger needs to be rapid and appropriate. In humans, nocifensive behaviors often precede conscious pain perception. Much is known about local spinal cord circuits for simple reflexive responses, but the mechanisms underlying more complex behaviors remain poorly understood. We now describe a brainstem circuit that controls escape responses to select noxious stimuli. Tracing experiments characterized a highly interconnected excitatory circuit involving the dorsal spinal cord, parabrachial nucleus (PBNl), and reticular formation (MdD). A combination of chemogenetic, optogenetic, and genetic ablation approaches revealed that PBNl neurons are activated by noxious stimuli and trigger robust escape responses to heat through connections to the MdD. Remarkably, MdD neurons receive excitatory input from the PBN and target both the spinal cord and PBN; activation of these neurons phenocopies the behavioral effects of PBNl neuron stimulation. These findings identify a substrate for controlling appropriate behavioral responses to painful stimuli.
Topics: Adenosine Triphosphate; Animals; Brain Stem; Calcitonin Gene-Related Peptide; Decerebrate State; Luminescent Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Neural Pathways; Nociceptors; Optogenetics; Pain; Pain Perception; Spinal Cord; Tachykinins; Transduction, Genetic
PubMed: 30449655
DOI: 10.1016/j.neuron.2018.10.037 -
The Journal of Pain Aug 2022The lateral parabrachial nucleus (LPBN) plays an important role in the processing and establishment of pain aversion. It receives direct input from the superficial...
The lateral parabrachial nucleus (LPBN) plays an important role in the processing and establishment of pain aversion. It receives direct input from the superficial dorsal horn and forms reciprocal connections with the periaqueductal grey matter (PAG), which is critical for adaptive behaviour and the modulation of pain processing. Here, using in situ hybridization and optogenetics combined with in vitro electrophysiology, we characterized the spinal- and PAG-LPBN circuits of rats. We found spinoparabrachial projections to be strictly glutamatergic, while PAG neurons send glutamatergic and GABAergic projections to the LPBN. We next investigated the effects of drugs with anti-aversive and/or anti-nociceptive properties on these synapses: The µ-opioid receptor agonist DAMGO (10 µM) reduced spinal and PAG synaptic inputs onto LPBN neurons, and the excitability of LPBN neurons receiving these inputs. The benzodiazepine receptor agonist diazepam (5 µM) strongly enhanced GABAergic action at inhibitory PAG-LPBN synapses. The cannabinoid receptor agonist WIN 55,212-2 (5 µM) led to a reduction in inhibitory and excitatory PAG-LPBN synaptic transmission, without affecting excitatory spinoparabrachial synaptic transmission. Our study reveals that opioid, cannabinoid and benzodiazepine receptor agonists differentially affect distinct LPBN synapses. These findings may support the efforts to develop pinpointed therapies for pain patients. PERSPECTIVE: The LPBN is an important brain region for the control of pain aversion versus recuperation, and as such constitutes a promising target for developing new strategies for pain management. We show that clinically-relevant drugs have complex and pathway-specific effects on LPBN processing of putative nociceptive and aversive inputs.
Topics: Analgesics, Opioid; Animals; Pain; Parabrachial Nucleus; Periaqueductal Gray; Rats; Rats, Sprague-Dawley; Receptors, GABA-A
PubMed: 35339662
DOI: 10.1016/j.jpain.2022.03.234 -
Neuron Jan 2023Proper sensing of ambient temperature is of utmost importance for the survival of euthermic animals, including humans. While considerable progress has been made in our...
Proper sensing of ambient temperature is of utmost importance for the survival of euthermic animals, including humans. While considerable progress has been made in our understanding of temperature sensors and transduction mechanisms, the higher-order neural circuits processing such information are still only incompletely understood. Using intersectional genetics in combination with circuit tracing and functional neuron manipulation, we identified Kcnip2-expressing inhibitory (Kcnip2) interneurons of the mouse spinal dorsal horn as critical elements of a neural circuit that tunes sensitivity to cold. Diphtheria toxin-mediated ablation of these neurons increased cold sensitivity without affecting responses to other somatosensory modalities, while their chemogenetic activation reduced cold and also heat sensitivity. We also show that Kcnip2 neurons become activated preferentially upon exposure to cold temperatures and subsequently inhibit spinal nociceptive output neurons that project to the lateral parabrachial nucleus. Our results thus identify a hitherto unknown spinal circuit that tunes cold sensitivity.
Topics: Humans; Mice; Animals; Cold Temperature; Spinal Cord Dorsal Horn; Neurons; Interneurons; Posterior Horn Cells; Kv Channel-Interacting Proteins
PubMed: 36323322
DOI: 10.1016/j.neuron.2022.10.008 -
ELife Feb 2022Long-lasting negative affections dampen enthusiasm for life, and dealing with negative affective states is essential for individual survival. The parabrachial nucleus...
Long-lasting negative affections dampen enthusiasm for life, and dealing with negative affective states is essential for individual survival. The parabrachial nucleus (PBN) and thalamic paraventricular nucleus (PVT) are critical for modulating affective states in mice. However, the functional roles of PBN-PVT projections in modulating affective states remain elusive. Here, we show that PBN neurons send dense projection fibers to the PVT and form direct excitatory synapses with PVT neurons. Activation of the PBN-PVT pathway induces robust behaviors associated with negative affective states without affecting nociceptive behaviors. Inhibition of the PBN-PVT pathway reduces aversion-like and fear-like behaviors. Furthermore, the PVT neurons innervated by the PBN are activated by aversive stimulation, and activation of PBN-PVT projections enhances the neuronal activity of PVT neurons in response to the aversive stimulus. Consistently, activation of PVT neurons that received PBN-PVT projections induces anxiety-like behaviors. Thus, our study indicates that PBN-PVT projections modulate negative affective states in mice.
Topics: Animals; Mice; Neurons; Parabrachial Nucleus; Synapses
PubMed: 35167440
DOI: 10.7554/eLife.68372 -
Cell Reports Apr 2023Mechanical allodynia (MA) represents one prevalent symptom of chronic pain. Previously we and others have identified spinal and brain circuits that transmit or modulate...
Mechanical allodynia (MA) represents one prevalent symptom of chronic pain. Previously we and others have identified spinal and brain circuits that transmit or modulate the initial establishment of MA. However, brain-derived descending pathways that control the laterality and duration of MA are still poorly understood. Here we report that the contralateral brain-to-spinal circuits, from Oprm1 neurons in the lateral parabrachial nucleus (lPBN), via Pdyn neurons in the dorsal medial regions of hypothalamus (dmH), to the spinal dorsal horn (SDH), act to prevent nerve injury from inducing contralateral MA and reduce the duration of bilateral MA induced by capsaicin. Ablating/silencing dmH-projecting lPBN neurons or SDH-projecting dmH neurons, deleting Dyn peptide from dmH, or blocking spinal κ-opioid receptors all led to long-lasting bilateral MA. Conversely, activation of dmH neurons or their axonal terminals in SDH can suppress sustained bilateral MA induced by lPBN lesion.
Topics: Mice; Animals; Hyperalgesia; Spinal Cord; Central Nervous System; Spinal Cord Dorsal Horn; Neurons; Hypothalamus
PubMed: 36952340
DOI: 10.1016/j.celrep.2023.112300 -
American Journal of Physiology.... Mar 2021Previously, we identified a population of neurons in the hindbrain tegmentum, bordering the locus coeruleus (LC). We named this population the pre-locus coeruleus...
Previously, we identified a population of neurons in the hindbrain tegmentum, bordering the locus coeruleus (LC). We named this population the pre-locus coeruleus (pre-LC) because in rats its neurons lie immediately rostral to the LC. In mice, however, pre-LC and LC neurons intermingle, making them difficult to distinguish. Here, we use molecular markers and anterograde tracing to clarify the location and distribution of pre-LC neurons in mice, relative to rats. First, we colocalized the transcription factor FoxP2 with the activity marker Fos to identify pre-LC neurons in sodium-deprived rats and show their distribution relative to surrounding catecholaminergic and cholinergic neurons. Next, we used sodium depletion and chemogenetic activation of the aldosterone-sensitive HSD2 neurons in the nucleus of the solitary tract (NTS) to identify the homologous population of pre-LC neurons in mice, along with a related population in the central lateral parabrachial nucleus. Using Cre-reporter mice for , we confirmed that most of these sodium-depletion-activated neurons are dynorphinergic. Finally, after confirming that these neurons receive excitatory input from the NTS and paraventricular hypothalamic nucleus, plus convergent input from the inhibitory AgRP neurons in the arcuate hypothalamic nucleus, we identify a major, direct input projection from the medial prefrontal cortex. This new information on the location, distribution, and input to pre-LC neurons provides a neuroanatomical foundation for cell-type-specific investigation of their properties and functions in mice. Pre-LC neurons likely integrate homeostatic information from the brainstem and hypothalamus with limbic, contextual information from the cerebral cortex to influence ingestive behavior.
Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Adrenergic Neurons; Animal Feed; Animals; Appetite Regulation; Basic Helix-Loop-Helix Transcription Factors; Biomarkers; Brain; Cholinergic Neurons; Diet, Sodium-Restricted; Enkephalins; Feeding Behavior; Female; Locus Coeruleus; Male; Mice, Inbred C57BL; Mice, Transgenic; Neural Pathways; Neuroanatomical Tract-Tracing Techniques; Neurons; Protein Precursors; Rats, Sprague-Dawley; Repressor Proteins; Mice; Rats
PubMed: 33296280
DOI: 10.1152/ajpregu.00261.2020 -
Molecular and Cellular Endocrinology Dec 2019Stress is well-known to inhibit a variety of reproductive processes, including the suppression of episodic Gonadotropin releasing hormone (GnRH) secretion, typically... (Review)
Review
Stress is well-known to inhibit a variety of reproductive processes, including the suppression of episodic Gonadotropin releasing hormone (GnRH) secretion, typically measured via downstream luteinizing hormone (LH) secretion. Since pulsatile secretion of GnRH and LH are necessary for proper reproductive function in both males and females, and stress is common for both human and animals, understanding the fundamental mechanisms by which stress impairs LH pulses is of critical importance. Activation of the hypothalamic-pituitary-adrenal axis, and its corresponding endocrine factors, is a key feature of the stress response, so dissecting the role of stress hormones, including corticotrophin releasing hormone (CRH) and corticosterone, in the inhibition of LH secretion has been one key research focus. However, some evidence suggests that these stress hormones alone are not sufficient for the full inhibition of LH caused by stress, implicating the additional involvement of other hormonal or neural signaling pathways in this process (including inputs from the brainstem, amygdala, parabrachial nucleus, and dorsomedial nucleus). Moreover, different stress types, such as metabolic stress (hypoglycemia), immune stress, and psychosocial stress, appear to suppress LH secretion via partially unique neural and endocrine pathways. The mechanisms underlying the suppression of LH pulses in these models offer interesting comparisons and contrasts, including the specific roles of amygdaloid nuclei and CRH receptor types. This review focuses on the most recent and emerging insights into endocrine and neural mechanisms responsible for the suppression of pulsatile LH secretion in mammals, and offers insights in important gaps in knowledge.
Topics: Animals; Endocrine System; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Nervous System; Stress, Physiological
PubMed: 31521706
DOI: 10.1016/j.mce.2019.110579