Neuronal activities that synchronize with the breathing rhythm have been found in humans and a host of mammalian species, not only in brain areas closely related to respiratory control or olfactory coding but also in areas linked to emotional and higher cognitive functions. In parallel, evidence is mounting for modulations of perception and action by the breathing cycle. In this Review, we discuss the extent to which brain activity locks to breathing across areas, levels of organization and brain states, and the physiological origins of this global synchrony. We describe how waves of sensory activity evoked by nasal airflow spread through brain circuits, synchronizing neuronal populations to the breathing cycle and modulating faster oscillations, cell assembly formation and cross-area communication, thereby providing a mechanistic link from breathing to neural coding, emotion and cognition. We argue that, through evolution, the breathing rhythm has come to shape network functions across species.

Acute stress results from sudden short-term events, and individuals need to quickly adjust their physiological and psychological to re-establish balance. Chronic stress, on the other hand, results in long-term physiological and psychological burdens due to the continued existence of stressors, making it difficult for individuals to recover and prone to pathological symptoms. Both types of stress can affect working memory and change cognitive function. In this study, we explored the impact of acute and chronic stress on synaptic modulation using a biologically inspired, data-driven rodent prefrontal neural network model. The model consists of a specific number of excitatory and inhibitory neurons that are connected through AMPA, NMDA, and GABA synapses. The study used a short-term recall to simulate working memory tasks and assess the ability of neuronal populations to maintain information over time. The results showed that acute stress can enhance working memory information retention by enhancing AMPA and NMDA synaptic currents. In contrast, chronic stress reduces dendritic spine density and weakens the regulatory effect of GABA currents on working memory tasks. In addition, this structural damage can be complemented by strong connections between excitatory neurons with the same selectivity. These findings provide a reference scheme for understanding the neural basis of working memory under different stress conditions.

Zebrafish have gained prominence as a model organism in neuroscience over the past several decades, generating key insight into the development and functioning of the vertebrate brain. However, techniques for whole brain mapping in adult stage zebrafish are lacking. Here, we describe a pipeline built using open-source tools for whole-brain activity mapping in adult zebrafish. Our pipeline combines advances in histology, microscopy, and machine learning to capture cfos activity across the entirety of the brain. Following tissue clearing, whole brain images are captured using light-sheet microscopy and registered to the recently created adult zebrafish brain atlas (AZBA) for automated segmentation. By way of example, we used our pipeline to measure brain activity after zebrafish were subject to the novel tank test, one of the most widely used behaviors in adult zebrafish. Cfos levels peaked 15 minutes following behavior and several regions, including those containing serotoninergic and dopaminergic neurons, were active during exploration. Finally, we generated a novel tank test functional brain network. This revealed that several regions of the subpallium form a cohesive sub-network during exploration. Functional interconnections between the subpallium and other regions appear to be mediated primarily by ventral nucleus of the ventral telencephalon (Vv), the olfactory bulb, and the anterior part of the parvocellular preoptic nucleus (PPa). Taken together, our pipeline enables whole-brain activity mapping in adult zebrafish while providing insight into neural basis for the novel tank test.Significance statement Zebrafish have grown in popularity as a model organism over the past several decades due to their low cost, ease of genetic manipulation, and similarity to other vertebrates like humans and rodents. However, to date, tools for whole-brain mapping in adult stage animals has been lacking. Here, we present an open-source pipeline for whole-brain mapping in adult zebrafish. We demonstrate the use of our pipeline by generating a functional brain network for one of the most widely used behavioral assays in adult zebrafish, the novel tank test. We found that exploration of a novel tank engages the olfactory bulb and a network of subpallial regions that correspond to the mammalian subpallial amygdala and basal ganglia.

Optogenetics and chemogenetics are emerging neuromodulation techniques that have attracted significant attention in recent years. These techniques enable the precise control of specific neuronal types and neural circuits, allowing researchers to investigate the cellular mechanisms underlying depression. The advancement in these techniques has significantly contributed to the understanding of the neural circuits involved in depression; when combined with other emerging technologies, they provide novel therapeutic targets and diagnostic tools for the clinical treatment of depression. Additionally, these techniques have provided theoretical support for the development of novel antidepressants. This review primarily focuses on the application of optogenetics and chemogenetics in several brain regions closely associated with depressive-like behaviors in rodent models, such as the ventral tegmental area, nucleus accumbens, prefrontal cortex, hippocampus, dorsal raphe nucleus, and lateral habenula and discusses the potential and challenges of optogenetics and chemogenetics in future research. Furthermore, this review discusses the potential and challenges these techniques pose for future research and describes the current state of research on sonogenetics and odourgenetics developed based on optogenetics and chemogenetics. Specifically, this study aimed to provide reliable insights and directions for future research on the role of optogenetics and chemogenetics in the neural circuits of depressive rodent models.

Depression is a prevalent and disabling disorder that poses serious problems in mental health care, and rapid antidepressants are novel treatments for this disorder. Cannabidiol (CBD), a nonintoxicating phytocannabinoid, is thought to have therapeutic potential due to its important neurological and anti-inflammatory properties. Despite major advances in pharmacotherapy in experimental animals, the exact mechanism of antidepressant-like effects remains to be elucidated.

In this paper, we review the current state of knowledge on the antidepressant properties of CBD in numerous experimental and clinical studies.

Accumulating evidence suggests that CBD has antidepressant properties in humans and animals with few side effects, suggesting that CBD may be a potential antidepressant. Furthermore, we discuss that CBD may therefore provide a potential treatment to exert antidepressant-like effects through various molecular targets, reducing inflammation, and enhancing neurogenesis.

Taken together with the growing popularity of CBD as a medicine, these findings extend the limited knowledge on the antidepressant effects of CBD. This potentially opens up new therapeutic means for the patients with depression.

Most organisms, including humans, show daily rhythms in many aspects of physiology and behavior, and abnormalities in the rhythms are potential risk factors for various diseases. Mood disorders such as depression are no exception. Accumulating evidence suggests strong associations between circadian disturbances and the development of depression. Numerous studies have shown that interventions to circadian rhythms trigger depression-like phenotypes in human cases and animal models. Conversely, mood changes can affect circadian rhythms as symptoms of depression. Our preliminary data suggest that the phosphorylation signal pathway of the clock protein may act as a common pathway for mood and clock regulation. We hypothesize that mood regulation and circadian rhythms may influence each other and may share a common regulatory mechanism. This review provides an overview of circadian disturbances in animal models and human patients with depression.

After olfactory bulbectomy, animals are often used as a model of major depression or sporadic Alzheimer's disease and, hence, the status of this model is still disputable. To elucidate the nature of alterations in the expression of the genome after the operation, we analyzed transcriptomes of the cortex, hippocampus, and cerebellum of the olfactory bulbectomized (OBX) mice. Analysis of the functional significance of genes in the brain of OBX mice indicates that the balance of the GABA/glutamatergic systems is disturbed with hyperactivation of the latter in the hippocampus, leading to the development of excitotoxicity and induction of apoptosis in the background of severe mitochondrial dysfunction and astrogliosis. On top of this, the synthesis of neurotrophic factors decreases leading to the disruption of the cytoskeleton of neurons, an increase in the level of intracellular calcium, and the activation of tau protein hyperphosphorylation. Moreover, the acetylcholinergic system is deficient in the background of the hyperactivation of acetylcholinesterase. Importantly, the activity of the dopaminergic, endorphin, and opiate systems in OBX mice decreases, leading to hormonal dysfunction. On the other hand, genes responsible for the regulation of circadian rhythms, cell migration, and innate immunity are activated in OBX animals. All this takes place in the background of a drastic downregulation of ribosomal protein genes in the brain. The obtained results indicate that OBX mice represent a model of Alzheimer's disease with elements of major depression.

Depressive disorder is a chronic, recurring, and potentially life-endangering neuropsychiatric disease. According to a report by the World Health Organization, the global population suffering from depression is experiencing a significant annual increase. Despite its prevalence and considerable impact on people, little is known about its pathogenesis. One major reason is the scarcity of reliable animal models due to the absence of consensus on the pathology and etiology of depression. Furthermore, the neural circuit mechanism of depression induced by various factors is particularly complex. Considering the variability in depressive behavior patterns and neurobiological mechanisms among different animal models of depression, a comparison between the neural circuits of depression induced by various factors is essential for its treatment. In this review, we mainly summarize the most widely used behavioral animal models and neural circuits under different triggers of depression, aiming to provide a theoretical basis for depression prevention.

Anxiety elicits various physiological responses, including changes in the respiratory rate and neuronal activity within specific brain regions such as the medial prefrontal cortex (mPFC). Previous research suggests that the olfactory bulb (OB) modulates the mPFC through respiration-coupled oscillations (RCOs), which have been linked to fear-related freezing behavior. Nevertheless, the impact of breathing on frontal brain networks during other negative emotional responses, such as anxiety-related states characterized by higher breathing rates, remains unclear. To address this, we subjected rats to the elevated plus maze (EPM) paradigm while simultaneously recording respiration and local field potentials in the OB and mPFC. Our findings demonstrate distinct respiratory patterns during EPM exploration: slower breathing frequencies prevailed in the closed arms, whereas faster frequencies were observed in the open arms, independent of locomotor activity, indicating that anxiety-like states are associated with increased respiratory rates. Additionally, we identified RCOs at different frequencies, mirroring the bimodal distribution of respiratory frequencies. RCOs exhibited higher power during open-arm exploration, when they showed greater coherence with breathing at faster frequencies. Furthermore, we confirmed that nasal respiration drives RCOs in frontal brain regions and found a stronger effect during faster breathing. Interestingly, we observed that the frequency of prefrontal gamma oscillations modulated by respiration increased with breathing frequency. Overall, our study provides evidence for a significant influence of breathing on prefrontal cortex networks during anxious states, shedding light on the complex interplay between respiratory physiology and emotional processing.

Inducing multiple neurobehavioural and neurochemical deficits, olfactory bulbectomy (OBX) has been developed as a rodent model of depression with potential for antidepressant drug screening. However, the generality of this model in other vertebrate taxa remains poorly understood. A small freshwater teleost fish, the zebrafish (Danio rerio), is rapidly becoming a common model species in neuroscience research. Capitalizing on a recently developed model of noninvasive targeted laser ablation of zebrafish brain, here we report an OBX model in adult fish. An easy-to-perform noninvasive method of inducing affective syndrome-like behavioural deficits in fish, it extends the generality of OBX to other taxa beyond mammals, also offering several practical advantages and novel lines of research in experimental modelling of CNS disorders. The work is a scientific tribute to the legacy of Brian Leonard (1936-2023), a great friend and a brilliant scientist who introduced OBX as a rodent model for affective pathobiology and whose advice and encouragement have inspired the present study.

We investigated the relationship between olfactory function and depression and suggested future research in this area from rhinology.

We independently searched 5 databases (PubMed, SCOPUS, Embase, the Web of Science, and the Cochrane database) for recent studies published from December 2019 to the present. From the obtained studies, we reviewed the findings on olfactory function and depression using a questionnaire to measure depression and olfactory tests.

The olfactory function test score based on the UPSIT-40 (standardized mean difference = -.37 [-.66; -.08], P = .0123) was significantly lower in the depression group than in the control group. The olfactory function score based on the Sniffin' sticks test for identification, discrimination, and threshold was lower in the depression group than in the control. A meta-analysis of the studies showed that depressed patients showed lower olfactory function than the control group.

The findings revealed that an understanding of the relationship between olfaction and depression can be determined using an analysis methodology and a standardized olfactory test. Olfactory functioning and processing are highly integrated with emotion and memory through projections from the olfactory bulb to the central areas.

Major depressive disorder (MDD) is a mental illness with a high worldwide prevalence and suboptimal pharmacological treatment, which necessitates the development of novel, more efficacious MDD medication. Nuclear magnetic resonance (NMR) can non-invasively provide insight into the neurochemical state of the brain using proton magnetic resonance spectroscopy (1H MRS), and an assessment of regional cerebral blood flow (rCBF) by perfusion imaging. These methods may provide valuable in vivo markers of the pathological processes underlying MDD.

This study examined the effects of the chronic antidepressant medication, citalopram, in a well-validated MDD model induced by bilateral olfactory bulbectomy (OB) in rats. 1H MRS was utilized to assess key metabolite ratios in the dorsal hippocampus and sensorimotor cortex bilaterally, and arterial spin labelling was employed to estimate rCBF in several additional brain regions.

The 1H MRS data results suggest lower hippocampal Cho/tCr and lower cortical NAA/tCr levels as a characteristic of the OB phenotype. Spectroscopy revealed lower hippocampal Tau/tCr in citalopram-treated rats, indicating a potentially deleterious effect of the drug. However, the significant OB model-citalopram treatment interaction was observed using 1H MRS in hippocampal mI/tCr, Glx/tCr and Gln/tCr, indicating differential treatment effects in the OB and control groups. The perfusion data revealed higher rCBF in the whole brain, hippocampus and thalamus in the OB rats, while citalopram appeared to normalise it without affecting the control group.

Collectively, 1H MRS and rCBF approaches demonstrated their capacity to capture an OB-induced phenotype and chronic antidepressant treatment effect in multiple brain regions.

Alcohol use disorder (AUD) poses a significant public health challenge. Individuals with AUD engage in chronic and excessive alcohol consumption, leading to cycles of intoxication, withdrawal, and craving behaviors. This review explores the involvement of the cortical amygdala (CoA), a cortical brain region that has primarily been examined in relation to olfactory behavior, in the expression of alcohol dependence and excessive alcohol drinking. While extensive research has identified the involvement of numerous brain regions in AUD, the CoA has emerged as a relatively understudied yet promising candidate for future study. The CoA plays a vital role in rewarding and aversive signaling and olfactory-related behaviors and has recently been shown to be involved in alcohol-dependent drinking in mice. The CoA projects directly to brain regions that are critically important for AUD, such as the central amygdala, bed nucleus of the stria terminalis, and basolateral amygdala. These projections may convey key modulatory signaling that drives excessive alcohol drinking in alcohol-dependent subjects. This review summarizes existing knowledge on the structure and connectivity of the CoA and its potential involvement in AUD. Understanding the contribution of this region to excessive drinking behavior could offer novel insights into the etiology of AUD and potential therapeutic targets.

Bisphenol A (BPA) is ubiquitous in plastics, which can modify and improve the applicability and durability of plastics. Previous laboratory studies have shown that BPA can trigger cognitive impairment and depression. The olfactory bulb (OB) is significantly related to cognition and depression. However, there is a deficiency in information on BPA-induced OB neurotoxicity. Therefore, we analyzed the OB tissues of male mice at the transcriptional level after BPA poisoning at four different levels of concentration (0, 0.01, 0.1, and 1 μg/mL). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and weighted gene co-expression network analysis (WGCNA) were used to screen critical pathways and core genes. The result demonstrated that the PI3K-AKT signaling pathway might play a crucial role in the effects of BPA on the OB. In addition, two genes of the PI3K-AKT signaling pathway, the colony stimulating factor-1 receptor (Csf1r) and the toll-like receptor 2 (Tlr2), were screened by the protein-protein interaction networks. Furthermore, molecular docking identified ceftolozane as a potential drug candidate that could counteract BPA-related OB neurotoxicity. Conclusively, our results confirmed that BPA induced OB damage in male mice through the PI3K-AKT pathway and proposed that ceftolozane might reduce BPA-induced OB neurotoxicity.

The olfactory bulb (OB), a major structure of the limbic system, has been understudied in human investigations of psychopathologies such as depression. To explore more directly the molecular features of the OB in depression, a global comparative proteome analysis was carried out with human post-mortem OB samples from 11 males having suffered from depression and 12 healthy controls. We identified 188 differentially abundant proteins (with adjusted p < 0.05) between depressed cases and controls. Gene ontology and gene enrichment analyses suggested that these proteins are involved in biological processes including the complement and coagulation cascades. Cell type enrichment analysis displayed a significant reduction in several canonical astrocytic proteins in OBs from depressed patients. Furthermore, using RNA-fluorescence in-situ hybridization, we observed a decrease in the percentage of ALDH1L1+ cells expressing canonical astrocytic markers including ALDOC, NFIA, GJA1 (connexin 43) and SLC1A3 (EAAT1). These results are consistent with previous reports of downregulated astrocytic marker expression in other brain regions in depressed patients. We also conducted a comparative phosphoproteomic analysis of OB samples and found a dysregulation of proteins involved in neuronal and astrocytic functions. To determine whether OB astrocytic abnormalities is specific to humans, we also performed proteomics on the OB of socially defeated male mice, a commonly used model of depression. Cell-type specific analysis revealed that in socially defeated animals, the most striking OB protein alterations were associated with oligodendrocyte-lineage cells rather than with astrocytes, highlighting an important species difference. Overall, this study further highlights cerebral astrocytic abnormalities as a consistent feature of depression in humans.

Depression and anxiety disorders are prevalent stress-related neuropsychiatric disorders and involve multiple molecular changes and dysfunctions across various brain regions. However, the specific and shared pathophysiological mechanisms occurring in these regions remain unclear. Previous research used a rat model of chronic mild stress (CMS) to segregate and identify depression-susceptible, anxiety-susceptible, and insusceptible groups; then the proteomes of six distinct brain regions (the hippocampus, prefrontal cortex, hypothalamus, pituitary, olfactory bulb, and striatum) were separately and quantitatively analyzed. To gain a comprehensive and systematic understanding of the molecular abnormalities, this study aimed to investigate and compare differential proteomics data from the six regions. Differentially expressed proteins (DEPs) were identified in between specific regions and across all regions and subjected to a series of bioinformatics analyses. Regional comparisons showed that stress-induced proteomic changes and corresponding gene ontology and pathway enrichments were largely distinct, attributable to differences in cell populations, protein compositions, and brain functions of these areas. Additionally, a notable degree of overlap in the significantly enriched terms was identified, potentially suggesting strong connections in the enrichment across different regions. Furthermore, intra-regional and inter-regional protein-protein interaction networks and drug-target-DEP networks were constructed. Integrated analysis of the three association networks in the six regions, along with the DisGeNET database, identified ten DEPs as potential targets for anti-depression/anxiety drugs. Collectively, these findings revealed commonalities and differences across different brain regions at the protein level induced by CMS, and identified several novel protein targets for the development of new therapeutics for depression and anxiety.

Repetitive transcranial magnetic stimulation (rTMS) emerged as a non-invasive brain stimulation technique in the treatment of psychiatric disorders. Both preclinical and clinical studies as well as systematic reviews provide a heterogeneous picture, particularly concerning the stimulation protocols used in rTMS. Here, we present a review of rTMS effects in rodent models of depressive-like symptoms with the aim to identify the most relevant factors that lead to an increased therapeutic success. The influence of different factors, such as the stimulation parameters (stimulus frequency and intensity, duration of stimulation, shape and positioning of the coil), symptom severity and individual characteristics (age, species and genetic background of the rodents), on the therapeutic success are discussed. Accumulating evidence indicates that rTMS ameliorates a multitude of depressive-like symptoms in rodent models, most effectively at high stimulation frequencies (≥5 Hz) especially in adult rodents with a pronounced pathological phenotype. The therapeutic success of rTMS might be increased in the future by considering these factors and using more standardized stimulation protocols.

Major depressive disorder, a prevalent and severe psychiatric condition, necessitates development of new and fast-acting antidepressants. Genetic suppression of astrocytic inwardly rectifying potassium channel 4.1 (Kir4.1) in the lateral habenula ameliorates depression-like phenotypes in mice. However, Kir4.1 remains an elusive drug target for depression. Here, we discovered a series of Kir4.1 inhibitors through high-throughput screening. Lys05, the most potent one thus far, effectively suppressed native Kir4.1 channels while displaying high selectivity against established targets for rapid-onset antidepressants. Cryogenic-electron microscopy structures combined with electrophysiological characterizations revealed Lys05 directly binds in the central cavity of Kir4.1. Notably, a single dose of Lys05 reversed the Kir4.1-driven depression-like phenotype and exerted rapid-onset (as early as 1 hour) antidepressant actions in multiple canonical depression rodent models with efficacy comparable to that of (S)-ketamine. Overall, we provided a proof of concept that Kir4.1 is a promising target for rapid-onset antidepressant effects.

Growing evidence suggests that activators of nuclear factor erythroid-derived 2-like 2 (Nrf2), such as sulforaphane, may represent promising novel pharmacological targets for conditions related to oxidative stress, including depressive disorder. Therefore, we conducted a study to explore the behavioral and biochemical effects of repeated (14 days) sulforaphane (SFN) treatment in the olfactory bulbectomy (OB) animal model of depression. An open field test (OFT), splash test (ST), and spontaneous locomotor activity test (LA) were used to assess changes in depressive-like behavior and the potential antidepressant-like activity of SFN. The OB model induced hyperactivity in mice during the OFT and LA as well as a temporary loss of self-care and motivation in the ST. The repeated administration of SFN (10 mg/kg) effectively reversed these behavioral changes in OB mice across all tests. Additionally, a biochemical analysis revealed that SFN (10 mg/kg) increased the total antioxidant capacity in the frontal cortex and serum of the OB model. Furthermore, SFN (10 mg/kg) significantly enhanced superoxide dismutase activity in the serum of OB mice. Overall, the present study is the first to demonstrate the antidepressant-like effects of repeated SFN (10 mg/kg) treatment in the OB model and indicates that these benefits may be linked to improved oxidative status.

One of the most important developments in psychopharmacology in the past decade has been the emergence of novel treatments for mood disorders, such as psilocybin for treatment-resistant depression. Psilocybin is most commonly found in different species of mushroom; however, the literature on mushroom and fungus extracts with potential antidepressant activity extends well beyond just psilocybin-containing mushrooms, and includes both psychedelic and non-psychedelic species. In the current review, we systematically review the preclinical literature on mushroom and fungus extracts, and their effects of animal models of depression and tests of antidepressant activity. The PICO structure, PRISMA checklist and the Cochrane Handbook for systematic reviews of intervention were used to guide the search strategy. A scoping search was conducted in electronic databases PubMed, CINAHL, Embase and Web of Science. The literature search identified 50 relevant and suitable published studies. These included 19 different species of mushrooms, as well as seven different species of other fungi. Nearly all studies reported antidepressant-like effects of treatment with extracts. Treatments were most commonly delivered orally, in both acute and chronically administered studies to predominantly male rodents. Multiple animal models of depression were used, the most common being unpredictable chronic mild stress, while the tail suspension test and forced swim test were most frequently used as standalone antidepressant screens. Details on each experiment with mushroom and fungus species are discussed in detail, while an evaluation is provided of the strengths and weaknesses of these studies.

Olfaction is the most ancient sense and is needed for food-seeking, danger protection, mating and survival. It is often the first sensory modality to perceive changes in the external environment, before sight, taste or sound. Odour molecules activate olfactory sensory neurons that reside on the olfactory epithelium in the nasal cavity, which transmits this odour-specific information to the olfactory bulb (OB), where it is relayed to higher brain regions involved in olfactory perception and behaviour. Besides odour processing, recent studies suggest that the OB extends its function into the regulation of food intake and energy balance. Furthermore, numerous hormone receptors associated with appetite and metabolism are expressed within the OB, suggesting a neuroendocrine role outside the hypothalamus. Olfactory cues are important to promote food preparatory behaviours and consumption, such as enhancing appetite and salivation. In addition, altered metabolism or energy state (fasting, satiety and overnutrition) can change olfactory processing and perception. Similarly, various animal models and human pathologies indicate a strong link between olfactory impairment and metabolic dysfunction. Therefore, understanding the nature of this reciprocal relationship is critical to understand how olfactory or metabolic disorders arise. This present review elaborates on the connection between olfaction, feeding behaviour and metabolism and will shed light on the neuroendocrine role of the OB as an interface between the external and internal environments. Elucidating the specific mechanisms by which olfactory signals are integrated and translated into metabolic responses holds promise for the development of targeted therapeutic strategies and interventions aimed at modulating appetite and promoting metabolic health.

Impaired olfactory function may be associated with the development of psychiatric disorders such as depression and anxiety; however, knowledge on the mechanisms underlying psychiatric disorders is incomplete. A reversible model of olfactory dysfunction, zinc sulfate (ZnSO4) nasal-treated mice, exhibit depression-like behavior accompanying olfactory dysfunction. Therefore, we investigated olfactory function and depression-like behaviors in ZnSO4-treated mice using the buried food finding test and tail suspension test, respectively; investigated the changes in the hippocampal microglial activity and neurogenesis in the dentate gyrus by immunohistochemistry; and evaluated the inflammation and microglial polarity related-proteins in the hippocampus using western blot study. On day 14 after treatment, ZnSO4-treated mice showed depression-like behavior in the tail suspension test and recovery of the olfactory function in the buried food finding test. In the hippocampus of ZnSO4-treated mice, expression levels of ionized calcium-binding adapter molecule 1 (Iba1), cluster of differentiation 40, inducible nitric oxide synthase, interleukin (IL)-1β, IL-6, tumor necrosis factor-α, cleaved caspase-3, as well as the number of Iba1-positive cells and cell body size increased, and arginase-1 expression and neurogenesis decreased. Except for the increased IL-6, these changes were prevented by a microglia activation inhibitor, minocycline. The findings suggest that neuroinflammation due to polarization of M1-type hippocampal microglia is involved in depression accompanied with olfactory dysfunction.

ANKRD11 (ankyrin repeat domain 11) is a chromatin regulator and the only gene associated with KBG syndrome, a rare neurodevelopmental disorder. We have previously shown that Ankrd11 regulates murine embryonic cortical neurogenesis. Here, we show a novel olfactory bulb phenotype in a KBG syndrome mouse model and two diagnosed patients. Conditional knockout of Ankrd11 in murine embryonic neural stem cells leads to aberrant postnatal olfactory bulb development and reduced size due to reduction of the olfactory bulb granule cell layer. We further show that the rostral migratory stream has incomplete migration of neuroblasts, reduced cell proliferation as well as aberrant differentiation of neurons. This leads to reduced neuroblasts and neurons in the olfactory bulb granule cell layer. In vitro, Ankrd11-deficient neural stem cells from the postnatal subventricular zone display reduced migration, proliferation, and neurogenesis. Finally, we describe two clinically and molecularly confirmed KBG syndrome patients with anosmia and olfactory bulb and groove hypo-dysgenesis/agenesis. Our report provides evidence that Ankrd11 is a novel regulator of olfactory bulb development and neuroblast migration. Moreover, our study highlights a novel clinical sign of KBG syndrome linked to ANKRD11 perturbations in mice and humans.

The aim of this study was to explore the role and mechanism of the olfactory bulb (OB) microglial P2X7 receptor (P2X7R) in allergic rhinitis (AR)-related depression, with the objective of identifying a potential clinical target. An AR mouse model was induced using ovalbumin (OVA), while chronic stress was employed to induce depression. The study used P2X7R-specific antagonists and OB microglia-specific P2X7R knockdown mice as crucial tools. The results showed that mice in the OVA + stress group exhibited more pronounced depressive-like phenotypes. Furthermore, there was an observed increase in microglial activation in the OB, followed by a rise in the level of inflammation. The pharmacological inhibition of P2X7R significantly mitigated the depression-like phenotype and the OB inflammatory response in OVA + stress mice. Notably, the specific knockdown of microglial P2X7R in the OB resulted in a similar effect, possibly linked to the regulation of IL-1β via the "ATP-P2X7R-Caspase 1" axis. These findings collectively demonstrate that microglial P2X7R in the OB acts as a direct effector molecule in AR-related depression, and its inhibition may offer a novel strategy for clinical prevention and treatment.

The olfactory bulbectomy (OBX) animal model of depression reproduces the behavioral and neurochemical changes observed in depressed patients. We assessed the therapeutic effects of the Jieyu Chufan (JYCF) capsule on OBX rats. JYCF ameliorated the hedonic and anxiety-like behavior of OBX rats and attenuated the cortical and hippocampal damage. JYCF enhanced the expression of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF2), and adiponectin (ADPN) in the cortex and hippocampus of OBX rats. JYCF also reduced cortisol levels and restored the levels of excitatory neurotransmitters, such as 5-hydroxytryptamine (5-HT), acetylcholine (ACH), and glutamic acid (Glu), in the brain tissue of OBX rats. Our results suggest that JYCF preserves the synaptic structure by increasing the levels of synaptophysin (SYN) and postsynaptic density protein 95 (PSD95) and alleviates the histological alterations of brain tissue by activating AKT/PKA-CREB-BDNF pathways, and by upregulating ADPN and FGF2 expression in OBX rats. JYCF exerts multiple therapeutic effects on depression, including modulating neurotransmitters, repairing neuronal damage, and maintaining synaptic integrity. These findings support the potential of JYCF as a novel antidepressant agent with therapeutic effects on depression and related neurological disorders.

We examined the relationship between baseline olfactory performance and incident significant depressive symptoms and longitudinal depression trajectories in well-functioning older adults. Inflammation and cognitive status were examined as potential mediators.

Older adults (n = 2 125, 71-82 years, 51% female, 37% Black) completed an odor identification task at Year 3 (our study baseline) of the Health, Aging, and Body Composition study. Cognitive assessments, depressive symptoms, and inflammatory markers were ascertained across multiple visits over 8 years. Discrete-time complementary log-log models, group-based trajectory models, and multivariable-adjusted multinomial logistic regression were employed to assess the relationship between baseline olfaction and incident depression and longitudinal depression trajectories. Mediation analysis assessed the influence of cognitive status on these relationships.

Individuals with lower olfaction had an increased risk of developing significant depressive symptoms at follow-up (hazard ratio = 1.04, 95% confidence interval [CI]: 1.00, 1.08). Of the 3 patterns of longitudinal depression scores identified (stable low, stable moderate, and stable high), poorer olfaction was associated with a 6% higher risk of membership in the stable moderate (relative risk ratio [RRR] = 1.06, 95% CI: 1.02, 1.10)/stable high (RRR = 1.06, 95% CI: 1.00, 1.12) groups, compared to the stable low group. Poor cognitive status, but not inflammation, partially mediated the relationship between olfactory performance and incident depression symptom severity.

Suboptimal olfaction could serve as a prognostic indicator of vulnerability for the development of late-life depression. These findings underscore the need for a greater understanding of olfaction in late-life depression and the demographic, cognitive, and biological factors that influence these relationships over time.

Major depressive disorder (MDD) is underlined by neurochemical changes in the brain. Proton magnetic resonance spectroscopy (1H MRS) is a useful tool for their examination as it provides information about the levels of metabolites. This review summarises the current knowledge of 1H MRS findings from rodent models of MDD, assesses the results from both a biological and a technical perspective, and identifies the main sources of bias. From a technical point of view, bias-introducing factors are the diversity of the measured volumes and their positioning in the brain, the data processing, and the metabolite concentration expression. The biological variables are strain, sex, and species, as well as the model itself, and in vivo vs. ex vivo exploration. This review identified some consistency in the 1H MRS findings in the models of MDD: lower levels of glutamine, glutamate + glutamine, and higher levels of myo-inositol and taurine in most of the brain regions of MDD models. This may suggest changes in regional metabolism, neuronal dysregulation, inflammation, and a compensatory effect reaction in the MDD rodent models.

Early life adversity (ELA) causes aberrant functioning of neural circuits affecting the health of an individual. While ELA-induced behavioural disorders resulting from sensory and cognitive disabilities can be assessed clinically, the neural mechanisms need to be probed using animal models by employing multi-pronged experimental approaches. As ELA can alter sensory perception, we investigated the effect of early weaning on murine olfaction. By implementing go/no-go odour discrimination paradigm, we observed olfactory learning and memory impairments in early life stressed (ELS) male mice. As olfactory bulb (OB) circuitry plays a critical role in odour learning, we studied the plausible changes in the OB of ELS mice. Lowered c-Fos activity in the external plexiform layer and a reduction in the number of dendritic processes of somatostatin-releasing, GABAergic interneurons (SOM-INs) in the ELS mice led us to hypothesise the underlying circuit. We recorded reduced synaptic inhibitory feedback on mitral/tufted (M/T) cells, in the OB slices from ELS mice, explaining the learning deficiency caused by compromised refinement of OB output. The reduction in synaptic inhibition was nullified by the photo-activation of ChR2-expressing SOM-INs in ELS mice. The role of SOM-INs was revealed by learning-dependent refinement of Ca2+dynamics quantified by GCaMP6f signals, which was absent in ELS mice. Further, the causal role of SOM-INs involving circuitry was investigated by optogenetic modulation during the odour discrimination learning. Photo-activating these neurons rescued the ELA-induced learning deficits. Conversely, photo-inhibition caused learning deficiency in control animals, while it completely abolished the learning in ELS mice, confirming the adverse effects mediated by SOM-INs. Our results thus establish the role of specific inhibitory circuit in pre-cortical sensory area in orchestrating ELA-dependent changes.

The ventral striatum is a reward center implicated in the pathophysiology of depression. It contains islands of Calleja, clusters of dopamine D3 receptor-expressing granule cells, predominantly in the olfactory tubercle (OT). These OT D3 neurons regulate self-grooming, a repetitive behavior manifested in affective disorders. Here we show that chronic restraint stress (CRS) induces robust depression-like behaviors in mice and decreases excitability of OT D3 neurons. Ablation or inhibition of these neurons leads to depression-like behaviors, whereas their activation ameliorates CRS-induced depression-like behaviors. Moreover, activation of OT D3 neurons has a rewarding effect, which diminishes when grooming is blocked. Finally, we propose a model that explains how OT D3 neurons may influence dopamine release via synaptic connections with OT spiny projection neurons (SPNs) that project to midbrain dopamine neurons. Our study reveals a crucial role of OT D3 neurons in bidirectionally mediating depression-like behaviors, suggesting a potential therapeutic target.

Mood disorders, including depressive and bipolar disorders, are the group of psychiatric disorders with the highest prevalence and disease burden. However, their pathophysiology remains poorly understood. Animal models are an extremely useful tool for the investigation of molecular mechanisms underlying these disorders. For psychiatric symptom assessment in animals, a meaningful behavioral phenotype is needed. Social behaviors constitute naturally occurring complex behaviors in rodents and can therefore serve as such a phenotype, contributing to insights into disorder related molecular changes. In this narrative review, we give a fundamental overview of social behaviors in laboratory rodents, as well as their underlying neuronal mechanisms and their assessment. Relevant behavioral and molecular changes in models for mood disorders are presented and an outlook on promising future directions is given.

Depression is a psychiatric disorder characterized by a marked decrease in reward sensitivity. By using the olfactory bulbectomy (OBX) model of depression, it was shown that OBX rats display enhanced drug-taking and seeking behaviors in a self-administration paradigm than sham-operated (SHAM) controls, and sex is an important regulating factor. To reveal potential strain effects, we compared the operant behavior of male and female Sprague-Dawley and Wistar OBX and SHAM rats trained to self-administer palatable food pellets. Results showed that Sprague-Dawley OBX rats of both sexes exhibited lower operant responding rates and food intake than SHAM controls. Food restriction increased responding in both OBX and SHAM groups. Female rats responded more than males, but the OBX lesion abolished this effect. In Wistar rats, bulbectomy lowered food self-administration only during the last training days. Food self-administration was not significantly affected in Wistar rats by sex. In summary, this study showed that bulbectomy significantly reduces operant responding and food intake in male and female Sprague-Dawley rats while inducing a mild reducing effect only in the Wistar strain. Strain-dependent effects were also observed in the modulating role of sex and food restriction on operant responding and palatable food intake.

Although the etiology of major depressive disorder remains poorly understood, reduced gamma oscillations is an emerging biomarker. Olfactory bulbectomy, an established model of depression that reduces limbic gamma oscillations, suffers from non-specific effects of structural damage. Here, we show that transient functional suppression of olfactory bulb neurons or their piriform cortex efferents decreased gamma oscillation power in limbic areas and induced depression-like behaviors in rodents. Enhancing transmission of gamma oscillations from olfactory bulb to limbic structures by closed-loop electrical neuromodulation alleviated these behaviors. By contrast, silencing gamma transmission by anti-phase closed-loop stimulation strengthened depression-like behaviors in naive animals. These induced behaviors were neutralized by ketamine treatment that restored limbic gamma power. Taken together, our results reveal a causal link between limbic gamma oscillations and depression-like behaviors in rodents. Interfering with these endogenous rhythms can affect behaviors in rodent models of depression, suggesting that restoring gamma oscillations may alleviate depressive symptoms.

Depression is associated with reduced olfactory function. This relationship is assumed to be based on either a reduced olfactory bulb volume or diminished functioning of higher cortical areas. As previous results are controversial, we aimed to re-evaluate central olfactory processing in depression. We recorded the BOLD signal of 21 patients with Major Depressive Disorder and 21 age and gender matched healthy controls during odor presentation. In addition, we measured the individual olfactory bulb volume, tested odor identification and odor threshold, and asked for hedonic odor perception. In both groups, odor presentation led to a pronounced activation of primary olfactory areas. However, secondary olfactory areas were significantly less activated in depressed individuals. The two groups did not differ in olfactory bulb volume. Our results point towards altered olfactory processing in patients in those regions that relate to sensory integration and attention allocation. Difficulties in cognitive processing could impact olfactory function in depression. We are therefore in favor of a top-down mechanism originating in higher cortical areas explaining parts of the relation between depression and olfaction.

For many species, the sense of smell is the most important sensory system for interacting with the environment and conspecifics. In contrast, the role of perception and communication of chemosensory information in humans has long been underestimated. The human sense of smell was considered less reliable, so that it was given less importance compared to visual and auditory sensory impressions. For some time now, a growing branch of research has been dealing with the role of the sense of sell in emotion and social communication, which is often only perceived subconsciously. This connection will be examine in more detail in this article. First, he basics regarding the structure and function of our olfactory system will be described for better understanding and classification. Then, with this background knowledge, the significance of olfaction for interpersonal communication and emotions will be discussed. Finally, we conclude that people suffering from olfactory disorders have specific impairments in their quality of life.

Olfactory dysfunction contributes to the psychopathology of mental illness. In this review, we describe the neurobiology of olfaction, and the most common olfactory alterations in several mental illnesses. We also highlight the role, hitherto underestimated, that the olfactory pathways play in the regulation of higher brain functions and its involvement in the pathophysiology of psychiatric disorders, as well as the effect of inflammation on neurogenesis as a possible mechanism involved in olfactory dysfunction in psychiatric conditions.

The olfactory deficits present in anxiety, depression, schizophrenia or bipolar disorder consist of specific alterations of different components of the sense of smell, mainly the identification of odours, as well as the qualifications of their hedonic valence (pleasant or unpleasant). Epidemiological findings have shown that both environmental factors, such as air pollutants, and inflammatory disease of the upper respiratory tract, can contribute to an increased risk of mental illness, at least in part, due to peripheral inflammatory mechanisms of the olfactory system. In this review, we describe the neurobiology of olfaction, and the most common olfactory function alterations in several psychiatric conditions and its role as a useful symptom for the differential diagnosis. We also highlight the effect of inflammation on neurogenesis as a possible mechanism involved in olfactory dysfunction in these psychiatric conditions.

Alzheimer's disease is associated with marked olfactory dysfunction observed in the early stages. Clinical studies reported that acetylcholinesterase inhibitor donepezil (DNP) attenuated this deficit; however, the underlying mechanism remains unclear. Herein, we aimed to examine the effects and underlying mechanisms of DNP on olfactory deficits in zinc sulfate (ZnSO₄) nasal-treated mice, which were used as a model of reversible olfactory impairment. We evaluated olfactory function using the buried food finding test and neurogenesis in the subventricular zone (SVZ) using immunohistochemistry. Finally, we measured the expression of doublecortin (DCX), neuronal nuclear antigen (NeuN), olfactory marker protein, tyrosine hydroxylase (TH), tryptophan hydroxylase 2, glutamic acid decarboxylase 67, p-α-synuclein (Ser129), α-synuclein, p-AMPK, p-p70S6 kinase (p70S6K) (Thr389), LC3 Ⅱ/Ⅰ, and p-p62 in the olfactory bulb (OB) by western blotting. On day 7 after treatment, ZnSO₄-treated mice exhibited prolonged time to find the buried food, cell proliferation enhancement in the SVZ, increased NeuN, p-α-synuclein (Ser129), and α-synuclein levels, and decreased DCX and TH levels in the OB; except for TH, these changes normalized on day 14 after treatment. Repeated administration of DNP prevented the ZnSO₄-induced changes on day 7 after treatment. Moreover, DNP increased p-AMPK and LC3 Ⅱ/Ⅰ, and decreased p-p70S6K and p-p62 (Ser351) levels in the OB, suggesting that DNP enhances autophagy in the OB. These findings indicate that DNP may help prevent olfactory dysfunction by autophagy that reduces α-synuclein aggregation via the AMPK/mTOC1 pathway.

The pristane-induced lupus (PIL) model is a useful tool for studying environmental-related systemic lupus erythematosus (SLE). However, neuropsychiatric manifestations in this model have not been investigated in detail. Because neuropsychiatric lupus (NPSLE) is an important complication of SLE, we investigated the neuropsychiatric symptoms in the PIL mouse model to evaluate its suitability for NPSLE studies.

PIL mice showed olfactory dysfunction accompanied by an anxiety- and depression-like phenotype at month 2 or 4 after pristane injection. The levels of cytokines (IL-1β, IFN-α, IFN-β, IL-10, IFN-γ, IL-6, TNF-α and IL-17A) and chemokines (CCL2 and CXCL10) in the brain and blood-brain barrier (BBB) permeability increased significantly from week 2 or month 1, and persisted throughout the observed course of the disease. Notably, IgG deposition in the choroid plexus and lateral ventricle wall were observed at month 1 and both astrocytes and microglia were activated. Persistent activation of astrocytes was detected throughout the observed course of the disease, while microglial activation diminished dramatically at month 4. Lipofuscin deposition, a sign of neuronal damage, was detected in cortical and hippocampal neurons from month 4 to 8.

PIL mice exhibit a series of characteristic behavioral deficits and pathological changes in the brain, and therefore might be suitable for investigating disease pathogenesis and for evaluating potential therapeutic targets for environmental-related NPSLE.

Major depressive disorder (MDD) is a multidimensional psychiatric disorder that is estimated to affect around 350 million people worldwide. Generating valid and effective animal models of depression is critical and has been challenging for neuroscience researchers. For preclinical studies, models based on stress exposure, such as unpredictable chronic mild stress (uCMS), are amongst the most reliable and used, despite presenting concerns related to the standardization of protocols and time consumption for operators. To overcome these issues, we developed an automated system to expose rodents to a standard uCMS protocol. Here, we compared manual (uCMS) and automated (auCMS) stress-exposure protocols. The data shows that the impact of the uCMS exposure by both methods was similar in terms of behavioral (cognition, mood, and anxiety) and physiological (cell proliferation and endocrine variations) measurements. Given the advantages of time and standardization, this automated method represents a step forward in this field of preclinical research.

We previously reported that endothelins (ETs) regulate tyrosine hydroxylase (TH) activity and expression in the olfactory bulb (OB) of normotensive and hypertensive animals. Applying an ET receptor type A (ETA) antagonist to the brain suggested that endogenous ETs bind to ET receptor type B (ETB) to elicit effects.

The aim of the present work was to evaluate the role of central ETB stimulation on the regulation of blood pressure (BP) and the catecholaminergic system in the OB of deoxycorticosterone acetate (DOCA)-salt hypertensive rats.

DOCA-salt hypertensive rats were infused for 7 days with cerebrospinal fluid or IRL-1620 (ETB receptor agonist) through a cannula placed in the lateral brain ventricle. Systolic BP (SBP) and heart rate were recorded by plethysmography. The expression of TH and its phosphorylated forms in the OB were determined by immunoblotting, TH activity by a radioenzymatic assay, and TH mRNA by quantitative real-time polymerase chain reaction.

Chronic administration of IRL-1620 decreased SBP in hypertensive rats but not in normotensive animals. Furthermore, the blockade of ETB receptors also decreased TH-mRNA in DOCA-salt rats, but it did not modify TH activity or protein expression.

These findings suggest that brain ETs through the activation of ETB receptors contribute to SBP regulation in DOCA-salt hypertension. However, the catecholaminergic system in the OB does not appear to be conclusively involved although mRNA TH was reduced. Present and previous findings suggest that in this salt-sensitive animal model of hypertension, the OB contributes to chronic BP elevation.