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Signal Transduction and Targeted Therapy Feb 2024Worldwide, the incidence of major depressive disorder (MDD) is increasing annually, resulting in greater economic and social burdens. Moreover, the pathological... (Review)
Review
Worldwide, the incidence of major depressive disorder (MDD) is increasing annually, resulting in greater economic and social burdens. Moreover, the pathological mechanisms of MDD and the mechanisms underlying the effects of pharmacological treatments for MDD are complex and unclear, and additional diagnostic and therapeutic strategies for MDD still are needed. The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis, but these hypothesis cannot completely explain the pathological mechanism of MDD. Even it is still hard to adopt only one hypothesis to completely reveal the pathogenesis of MDD, thus in recent years, great progress has been made in elucidating the roles of multiple organ interactions in the pathogenesis MDD and identifying novel therapeutic approaches and multitarget modulatory strategies, further revealing the disease features of MDD. Furthermore, some newly discovered potential pharmacological targets and newly studied antidepressants have attracted widespread attention, some reagents have even been approved for clinical treatment and some novel therapeutic methods such as phototherapy and acupuncture have been discovered to have effective improvement for the depressive symptoms. In this work, we comprehensively summarize the latest research on the pathogenesis and diagnosis of MDD, preventive approaches and therapeutic medicines, as well as the related clinical trials.
Topics: Humans; Depressive Disorder, Major; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System
PubMed: 38331979
DOI: 10.1038/s41392-024-01738-y -
Frontiers in Endocrinology 2023Cognitive function in humans depends on the complex and interplay between multiple body systems, including the hypothalamic-pituitary-adrenal (HPA) axis. The gut... (Review)
Review
Cognitive function in humans depends on the complex and interplay between multiple body systems, including the hypothalamic-pituitary-adrenal (HPA) axis. The gut microbiota, which vastly outnumbers human cells and has a genetic potential that exceeds that of the human genome, plays a crucial role in this interplay. The microbiota-gut-brain (MGB) axis is a bidirectional signalling pathway that operates through neural, endocrine, immune, and metabolic pathways. One of the major neuroendocrine systems responding to stress is the HPA axis which produces glucocorticoids such as cortisol in humans and corticosterone in rodents. Appropriate concentrations of cortisol are essential for normal neurodevelopment and function, as well as cognitive processes such as learning and memory, and studies have shown that microbes modulate the HPA axis throughout life. Stress can significantly impact the MGB axis the HPA axis and other pathways. Animal research has advanced our understanding of these mechanisms and pathways, leading to a paradigm shift in conceptual thinking about the influence of the microbiota on human health and disease. Preclinical and human trials are currently underway to determine how these animal models translate to humans. In this review article, we summarize the current knowledge of the relationship between the gut microbiota, HPA axis, and cognition, and provide an overview of the main findings and conclusions in this broad field.
Topics: Animals; Humans; Gastrointestinal Microbiome; Hypothalamo-Hypophyseal System; Brain; Hydrocortisone; Pituitary-Adrenal System; Cognition
PubMed: 37404311
DOI: 10.3389/fendo.2023.1130689 -
Science (New York, N.Y.) Oct 2023During pregnancy, physiological adaptations prepare the female body for the challenges of motherhood. Becoming a parent also requires behavioral adaptations. Such...
During pregnancy, physiological adaptations prepare the female body for the challenges of motherhood. Becoming a parent also requires behavioral adaptations. Such adaptations can occur as early as during pregnancy, but how pregnancy hormones remodel parenting circuits to instruct preparatory behavioral changes remains unknown. We found that action of estradiol and progesterone on galanin (Gal)-expressing neurons in the mouse medial preoptic area (MPOA) is critical for pregnancy-induced parental behavior. Whereas estradiol silences MPOA neurons and paradoxically increases their excitability, progesterone permanently rewires this circuit node by promoting dendritic spine formation and recruitment of excitatory synaptic inputs. This MPOA-specific neural remodeling sparsens population activity in vivo and results in persistently stronger, more selective responses to pup stimuli. Pregnancy hormones thus remodel parenting circuits in anticipation of future behavioral need.
Topics: Animals; Female; Mice; Pregnancy; Estradiol; Maternal Behavior; Parenting; Preoptic Area; Progesterone; Models, Animal; Neurons
PubMed: 37797007
DOI: 10.1126/science.adi0576 -
Cell Metabolism Feb 2024Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through...
Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through inter-tissue communications. We have identified a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMH neurons), that regulates aging and longevity in mice. DMH neurons regulate physical activity and WAT function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), through sympathetic nervous stimulation. Within DMH neurons, the phosphorylation and subsequent nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase G (PKG; Prkg1), affect gene expression regulating synaptic function, causing synaptic transmission dysfunction and impaired WAT function. Both DMH-specific Prkg1 knockdown, which suppresses age-associated Ppp1r17 translocation, and the chemogenetic activation of DMH neurons significantly ameliorate age-associated dysfunction in WAT, increase physical activity, and extend lifespan. Thus, these findings clearly demonstrate the importance of the inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control.
Topics: Mice; Animals; Longevity; Aging; Neurons; Synaptic Transmission; Adipose Tissue; Hypothalamus; Dorsomedial Hypothalamic Nucleus; Mammals; Cyclic GMP-Dependent Protein Kinase Type I
PubMed: 38194970
DOI: 10.1016/j.cmet.2023.12.011 -
Arquivos de Neuro-psiquiatria Jul 2023The human gut microbiota is a complex ecosystem made of trillions of microorganisms. The composition can be affected by diet, metabolism, age, geography, stress,... (Review)
Review
The human gut microbiota is a complex ecosystem made of trillions of microorganisms. The composition can be affected by diet, metabolism, age, geography, stress, seasons, temperature, sleep, and medications. The increasing evidence about the existence of a close and bi-directional correlation between the gut microbiota and the brain indicates that intestinal imbalance may play a vital role in the development, function, and disorders of the central nervous system. The mechanisms of interaction between the gut-microbiota on neuronal activity are widely discussed. Several potential pathways are involved with the brain-gut-microbiota axis, including the vagus nerve, endocrine, immune, and biochemical pathways. Gut dysbiosis has been linked to neurological disorders in different ways that involve activation of the hypothalamic-pituitary-adrenal axis, imbalance in neurotransmitter release, systemic inflammation, and increase in the permeability of the intestinal and the blood-brain barrier. Mental and neurological diseases have become more prevalent during the coronavirus disease 2019pandemic and are an essential issue in public health globally. Understanding the importance of diagnosing, preventing, and treating dysbiosis is critical because gut microbial imbalance is a significant risk factor for these disorders. This review summarizes evidence demonstrating the influence of gut dysbiosis on mental and neurological disorders.
Topics: Humans; Dysbiosis; Hypothalamo-Hypophyseal System; Ecosystem; Pituitary-Adrenal System; Mental Disorders; Brain; Nervous System Diseases; Gastrointestinal Microbiome
PubMed: 37402401
DOI: 10.1055/s-0043-1767818 -
Nature Sep 2023Oxytocin is a neuropeptide that is important for maternal physiology and childcare, including parturition and milk ejection during nursing. Suckling triggers the release...
Oxytocin is a neuropeptide that is important for maternal physiology and childcare, including parturition and milk ejection during nursing. Suckling triggers the release of oxytocin, but other sensory cues-specifically, infant cries-can increase the levels of oxytocin in new human mothers, which indicates that cries can activate hypothalamic oxytocin neurons. Here we describe a neural circuit that routes auditory information about infant vocalizations to mouse oxytocin neurons. We performed in vivo electrophysiological recordings and photometry from identified oxytocin neurons in awake maternal mice that were presented with pup calls. We found that oxytocin neurons responded to pup vocalizations, but not to pure tones, through input from the posterior intralaminar thalamus, and that repetitive thalamic stimulation induced lasting disinhibition of oxytocin neurons. This circuit gates central oxytocin release and maternal behaviour in response to calls, providing a mechanism for the integration of sensory cues from the offspring in maternal endocrine networks to ensure modulation of brain state for efficient parenting.
Topics: Animals; Female; Mice; Cues; Hypothalamus; Maternal Behavior; Neural Pathways; Neurons; Oxytocin; Photometry; Thalamic Nuclei; Vocalization, Animal; Wakefulness
PubMed: 37730989
DOI: 10.1038/s41586-023-06540-4 -
Nature Neuroscience Jul 2023Excitatory projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) drive aversive responses. We used patch-sequencing (Patch-seq) guided...
Excitatory projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) drive aversive responses. We used patch-sequencing (Patch-seq) guided multimodal classification to define the structural and functional heterogeneity of the LHA-LHb pathway. Our classification identified six glutamatergic neuron types with unique electrophysiological properties, molecular profiles and projection patterns. We found that genetically defined LHA-LHb neurons signal distinct aspects of emotional or naturalistic behaviors, such as estrogen receptor 1-expressing (Esr1) LHA-LHb neurons induce aversion, whereas neuropeptide Y-expressing (Npy) LHA-LHb neurons control rearing behavior. Repeated optogenetic drive of Esr1 LHA-LHb neurons induces a behaviorally persistent aversive state, and large-scale recordings showed a region-specific neural representation of the aversive signals in the prelimbic region of the prefrontal cortex. We further found that exposure to unpredictable mild shocks induced a sex-specific sensitivity to develop a stress state in female mice, which was associated with a specific shift in the intrinsic properties of bursting-type Esr1 LHA-LHb neurons. In summary, we describe the diversity of LHA-LHb neuron types and provide evidence for the role of Esr1 neurons in aversion and sexually dimorphic stress sensitivity.
Topics: Female; Mice; Animals; Habenula; Hypothalamus; Hypothalamic Area, Lateral; Neurons; Affect; Neural Pathways
PubMed: 37349481
DOI: 10.1038/s41593-023-01367-8 -
Cells Nov 2023Cortisol, a critical glucocorticoid hormone produced by the adrenal glands, plays a pivotal role in various physiological processes. Its release is finely orchestrated... (Review)
Review
Cortisol, a critical glucocorticoid hormone produced by the adrenal glands, plays a pivotal role in various physiological processes. Its release is finely orchestrated by the suprachiasmatic nucleus, governing the circadian rhythm and activating the intricate hypothalamic-pituitary-adrenal (HPA) axis, a vital neuroendocrine system responsible for stress response and maintaining homeostasis. Disruptions in cortisol regulation due to chronic stress, disease, and aging have profound implications for multiple bodily systems. Animal models have been instrumental in elucidating these complex cortisol dynamics during stress, shedding light on the interplay between physiological, neuroendocrine, and immune factors in the stress response. These models have also revealed the impact of various stressors, including social hierarchies, highlighting the role of social factors in cortisol regulation. Moreover, chronic stress is closely linked to the progression of neurodegenerative diseases, like Alzheimer's and Parkinson's, driven by excessive cortisol production and HPA axis dysregulation, along with neuroinflammation in the central nervous system. The relationship between cortisol dysregulation and major depressive disorder is complex, characterized by HPA axis hyperactivity and chronic inflammation. Lastly, chronic pain is associated with abnormal cortisol patterns that heighten pain sensitivity and susceptibility. Understanding these multifaceted mechanisms and their effects is essential, as they offer insights into potential interventions to mitigate the detrimental consequences of chronic stress and cortisol dysregulation in these conditions.
Topics: Animals; Hydrocortisone; Depressive Disorder, Major; Neurodegenerative Diseases; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System
PubMed: 38067154
DOI: 10.3390/cells12232726 -
Philosophical Transactions of the Royal... Oct 2023The relationship between high body weight and mental health has been studied for several decades. Improvements in the quality of epidemiological, mechanistic and... (Review)
Review
The relationship between high body weight and mental health has been studied for several decades. Improvements in the quality of epidemiological, mechanistic and psychological research have brought greater consistency to our understanding of the links. Large-scale population-based epidemiological research has established that high body weight is associated with poorer mental health, particularly depression and subclinical depressive symptoms. There is some evidence for bidirectional relationships, but the most convincing findings are that greater body weight leads to psychological distress rather than the reverse. Particular symptoms of depression and distress may be specifically related to greater body weight. The psychological stress induced by weight stigma and discrimination contributes to psychological distress, and may in turn handicap efforts at weight control. Heightened systemic inflammation and dysregulation of the hypothalamic-pituitary-adrenal axis are biological mechanisms that mediate in part the relationship of greater body weight with poorer mental health. Changing negative societal attitudes to high body weights would improve the wellbeing of people living with obesity, and promote more effective weight-inclusive attitudes and behaviours in society at large, particularly in healthcare settings. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.
Topics: Humans; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Obesity; Psychological Distress; Mental Health
PubMed: 37661745
DOI: 10.1098/rstb.2022.0225 -
Cell Reports Oct 2023Chronic stress and chronic pain are two major predisposing factors to trigger depression. Enhanced excitatory input to the lateral habenula (LHb) has been implicated in...
Chronic stress and chronic pain are two major predisposing factors to trigger depression. Enhanced excitatory input to the lateral habenula (LHb) has been implicated in the pathophysiology of depression. However, the contribution of inhibitory transmission remains unclear. Here, we dissect an inhibitory projection from the sensory thalamic reticular nucleus (sTRN) to the LHb, which is activated by acute aversive stimuli. However, chronic restraint stress (CRS) weakens sTRN-LHb synaptic strength, and this synaptic attenuation is indispensable for CRS-induced LHb neural hyperactivity and depression onset. Moreover, artificially inhibiting the sTRN-LHb circuit induces depressive-like behaviors in healthy mice, while enhancing this circuit relieves depression induced by both chronic stress and chronic pain. Intriguingly, neither neuropathic pain nor comorbid mechanical hypersensitivity in chronic stress is affected by this pathway. Altogether, our study demonstrates an sTRN-LHb circuit in establishing and modulating depression, thus shedding light on potential therapeutic targets for preventing or managing depression.
Topics: Mice; Animals; Depression; Neurons; Habenula; Chronic Pain; Thalamic Nuclei
PubMed: 37738124
DOI: 10.1016/j.celrep.2023.113170