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Background: While Alzheimer's disease (AD) has been extensively studied with a focus on cognitive networks, visual network dysfunction has received less attention despite compelling evidence of its significance in AD patients and mouse models. We recently reported c-Fos and synaptic dysregulation in the primary visual cortex of a pre-amyloid plaque AD-model. Objective: We test whether c-Fos expression and presynaptic density/dynamics differ in cortical and subcortical visual areas in an AD-model. We also examine whether aberrant c-Fos expression is inherited through functional connectivity and shaped by light experience. Methods: c-Fos+ cell density, functional connectivity, and their experience-dependent modulation were assessed for visual and whole-brain networks in both sexes of 4-6-month-old J20 (AD-model) and wildtype (WT) mice. Cortical and subcortical differences in presynaptic vulnerability in the AD-model were compared using ex vivo and in vivo imaging. Results: Visual cortical, but not subcortical, networks show aberrant c-Fos expression and impaired experience-dependent modulation. The average functional connectivity of a brain region in WT mice significantly predicts aberrant c-Fos expression, which correlates with impaired experience-dependent modulation in the AD-model. We observed a subtle yet selective weakening of excitatory visual cortical synapses. The size distribution of cortical boutons in the AD-model is downscaled relative to those in WT mice, suggesting a synaptic scaling-like adaptation of bouton size. Conclusions: Visual network structural and functional disruptions are biased toward cortical regions in pre-plaque J20 mice, and the cellular and synaptic dysregulation in the AD-model represents a maladaptive modification of the baseline physiology seen in WT conditions.
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Introduction: The social defeat paradigm is the most representative animal model to study social anxiety disorder (SAD) and its underlying neuronal mechanisms. We have previously reported that defeat progressively reduces oxytocin receptors (OXTR) in limbic regions of the brain over an eight-week period in female prairie voles (Microtus ochrogaster). Oxytocin receptors activate the mitogen-activated protein kinase (MAPK) pathway, which has been previously associated with the anxiolytic effects of oxytocin. Here, we assessed the functional significance of OXTR in stress-induced social avoidance and the response of the MAPK signaling pathway in the nucleus accumbens (NAc), anterior cingulate cortex (ACC), and basolateral amygdala (BLA) of female prairie voles. Methods: In experiment 1, Sexually naïve adult female prairie voles were defeated for three consecutive days and tested a week after for social preference/avoidance (SPA) test. Control subjects were similarly handled without defeat conditioning. In experiment 2, sexually and stress naïve adult female prairie voles were bilaterally injected into the NAc, ACC, or the BLA with a CRISPR/Cas9 virus targeting the Oxtr coding sequence to induce OXTR knockdown. Two weeks post-surgery, subjects were tested for SPA behavior. Viral control groups were similarly handled but injected with a control virus. A subgroup of animals from each condition in both experiments were similarly treated and euthanized without being tested for SPA behavior. Brains were harvested for OXTR autoradiography, western blot analysis of MAPK proteins and quantification of local oxytocin content in the NAc, BLA, ACC, and PVN through ELISA. Results: Social defeat reduced OXTR binding in the NAc and affected MAPK pathway activity and oxytocin availability. These results were region-specific and sensitive to exposure to the SPA test. Additionally, OXTR knockdown in the NAc, ACC, and BLA induced social avoidance and decreased basal MAPK activity in the NAc. Finally, we found that OXTR knockdown in these regions was associated with less availability of oxytocin in the PVN. Conclusion: Dysregulation of the oxytocin system and MAPK signaling pathway in the NAc, ACC, and BLA are important in social behavior disruptions in female voles. This dysregulation could, therefore, play an important role in the etiology of SAD in women.
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Clusterin is a secreted glycoprotein that participates in multiple physiological processes through its chaperon function. In Alzheimer's disease, the brain functions under an increased oxidative stress condition that causes an elevation of protein oxidation, resulting in enhanced pathology. Accordingly, it is important to determine the type of human brain cells that are mostly prone to methionine oxidation in Alzheimer's disease and specifically monitoring the methionine-oxidation levels of clusterin in human and mice brains and its effect on clusterin's function. We analyzed the level of methionine sulfoxide (MetO)-clusterin in these brains, using a combination of immunoprecipitation and Western-blott analyses. Also, we determine the effect of methionine oxidation on clusterin ability to bind beta-amyloid, in vitro, using calorimetric assay. Our results show that human neurons and astrocytes of Alzheimer's disease brains are mostly affected by methionine oxidation. Moreover, MetO-clusterin levels are elevated in postmortem Alzheimer's disease human and mouse brains in comparison to controls. Finally, oxidation of methionine residues of purified clusterin reduced its binding efficiency to beta-amyloid. In conclusion, we suggest that methionine oxidation of brain-clusterin is enhanced in Alzheimer's disease and that this oxidation compromises its chaperon function, leading to exacerbation of beta-amyloid's toxicity in Alzheimer's disease.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Astrocitos , Encéfalo , Clusterina , Metionina , Oxidación-Reducción , Clusterina/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Metionina/metabolismo , Metionina/análogos & derivados , Humanos , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/metabolismo , Astrocitos/metabolismo , Ratones , Neuronas/metabolismo , Unión Proteica , Masculino , AncianoRESUMEN
Death of a loved one is recognized as one of life's greatest stresses, and 10%-20% of bereaved individuals will experience a complicated or prolonged grieving period that is characterized by intense yearning for the deceased. The monogamous prairie vole (Microtus ochrogaster) is a rodent species that forms pair bonds between breeding partners and has been used to study the neurobiology of social behaviors and isolation. Male prairie voles do not display distress after isolation from a familiar, same-sex conspecific; however, separation from a bonded female partner increases emotional, stress-related, and proximity-seeking behaviors. Here, we tested the investigatory response of male voles to partner odor during a period of social loss. We found that males who lost their partner spent significantly more time investigating partner odor but not non-partner social odor or food odor. Bachelor males and males in intact pairings did not respond uniquely to any odor. Furthermore, we examined dopamine (DA) receptor mRNA expression in the anterior insula cortex (aIC), nucleus accumbens (NAc), and anterior cingulate (ACC), regions with higher activation in grieving humans. While we found some effects of relationship type on DRD1 and DRD2 expression in some of these regions, loss of a high-quality opposite-sex relationship had a significant effect on DA receptor expression, with pair-bonded/loss males having higher expression in the aIC and ACC compared with pair-bonded/intact and nonbonded/loss males. Together, these data suggest that both relationship type and relationship quality affect reunion-seeking behavior and motivational neurocircuits following social loss of a bonded partner.
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Dopamina , Pradera , Humanos , Animales , Masculino , Femenino , Dopamina/metabolismo , Sistema Límbico/metabolismo , Núcleo Accumbens/metabolismo , Conducta Social , Arvicolinae/genéticaRESUMEN
The brain during Alzheimer's disease (AD) is under severe oxidative attack by reactive oxygen species that may lead to methionine oxidation. Oxidation of the sole methionine (Met35) of beta-amyloid (Aß), and possibly methionine residues of other extracellular proteins, may be one of the earliest events contributing to the toxicity of Aß and other proteins in vivo. In the current study, we immunized transgenic AD (APP/PS1) mice at 4 months of age with a recombinant methionine sulfoxide (MetO)-rich protein from Zea mays (antigen). This treatment induced the production of anti-MetO antibody in blood-plasma that exhibits a significant titer up to at least 10 months of age. Compared to the control mice, the antigen-injected mice exhibited the following significant phenotypes at 10 months of age: better short and long memory capabilities; reduced Aß levels in both blood-plasma and brain; reduced Aß burden and MetO accumulations in astrocytes in hippocampal and cortical regions; reduced levels of activated microglia; and elevated antioxidant capabilities (through enhanced nuclear localization of the transcription factor Nrf2) in the same brain regions. These data collected in a preclinical AD model are likely translational, showing that active immunization could give a possibility of delaying or preventing AD onset. This study represents a first step toward the complex way of starting clinical trials in humans and conducting the further confirmations that are needed to go in this direction.
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In social species such as humans, non-human primates, and even many rodent species, social interaction and the maintenance of social bonds are necessary for mental and physical health and wellbeing. In humans, perceived isolation, or loneliness, is not only characterized by physical isolation from peers or loved ones, but also involves negative perceptions about social interactions and connectedness that reinforce the feelings of isolation and anxiety. As a complex behavioral state, it is no surprise that loneliness and isolation are associated with dysfunction within the ventral striatum and the limbic system - brain regions that regulate motivation and stress responsiveness, respectively. Accompanying these neural changes are physiological symptoms such as increased plasma and urinary cortisol levels and an increase in stress responsivity. Although studies using animal models are not perfectly analogous to the uniquely human state of loneliness, studies on the effects of social isolation in animals have observed similar physiological symptoms such as increased corticosterone, the rodent analog to human cortisol, and also display altered motivation, increased stress responsiveness, and dysregulation of the mesocortical dopamine and limbic systems. This review will discuss behavioral and neuropsychological components of loneliness in humans, social isolation in rodent models, and the neurochemical regulators of these behavioral phenotypes with a neuroanatomical focus on the corticostriatal and limbic systems. We will also discuss social loss as a unique form of social isolation, and the consequences of bond disruption on stress-related behavior and neurophysiology.
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Complex social behaviors are governed by a neural network theorized to be the social decision-making network (SDMN). However, this theoretical network is not tested on functional grounds. Here, we assess the organization of regions in the SDMN using c-Fos, to generate functional connectivity models during specific social interactions in a socially monogamous rodent, the prairie voles (Microtus ochrogaster). Male voles displayed robust selective affiliation toward a female partner, while exhibiting increased threatening, vigilant, and physically aggressive behaviors toward novel males and females. These social interactions increased c-Fos levels in eight of the thirteen brain regions of the SDMN. Each social encounter generated a distinct correlation pattern between individual brain regions. Thus, hierarchical clustering was used to characterize interrelated regions with similar c-Fos activity resulting in discrete network modules. Functional connectivity maps were constructed to emulate the network dynamics resulting from each social encounter. Our partner functional connectivity network presents similarities to the theoretical SDMN model, along with connections in the network that have been implicated in partner-directed affiliation. However, both stranger female and male networks exhibited distinct architecture from one another and the SDMN. Further, the stranger-evoked networks demonstrated connections associated with threat, physical aggression, and other aversive behaviors. Together, this indicates that distinct patterns of functional connectivity in the SDMN can be detected during select social encounters.
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Social anxiety disorder (SAD) is a prevalent mental illness in both men and women, but current treatment approaches with selective serotonin reuptake inhibitors (SSRI) have limited success. The neuropeptide oxytocin (OXT) has become a therapeutic target due to its prosocial and anxiolytic effects. Nevertheless, no research has focused on the impact of chronic OXT treatment in animal models of SAD. Social defeat stress is an animal model of social conflict that reliably induces a social avoidance phenotype, reflecting symptoms observed in individuals suffering from SAD. Here, we used the socially monogamous prairie vole, which exhibits aggressive behavior in both sexes, to examine the effects of OXT and SSRI treatment following social defeat stress in males and females. Defeated voles became avoidant in unfamiliar social situations as early as one day after defeat experience, and this phenotype persisted for at least eight weeks. OXT receptor (OXTR) binding in mesocorticolimbic and paralimbic regions was reduced in defeated females during the eight-week recovery period. In males, serotonin 1A receptor binding was decreased in the basolateral amygdala and dorsal raphe nucleus starting at one week and four weeks post-defeat, respectively. Chronic intranasal treatment with OXT had a negative effect on sociability and mesolimbic OXTR binding in non-defeated females. However, chronic intranasal OXT promoted social engagement and increased mesolimbic OXTR binding in defeated females but not males. SSRI treatment led to only modest effects. This study identifies a sex-specific and stress-dependent function of intranasal OXT on mesolimbic OXTR and social behaviors.
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Arvicolinae/fisiología , Oxitocina/administración & dosificación , Oxitocina/uso terapéutico , Conducta Social , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/psicología , Administración Intranasal , Agresión/efectos de los fármacos , Animales , Ansiedad , Femenino , Sistema Límbico/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Oxitocina/metabolismoAsunto(s)
Miedo/fisiología , Oxitocina/metabolismo , Dolor/metabolismo , Estrés Psicológico/metabolismo , Animales , HumanosRESUMEN
Chronic sympathetic nervous system (SNS) overactivity, characteristic of heart failure (HF) with reduced ejection fraction (HFrEF), is associated with poor prognosis and contributes to increased mortality risk. Sacubitril-valsartan is a recently approved, first-in-class, angiotensin receptor neprilysin inhibitor (ARNI) drug that markedly reduces the risks of death from cardiovascular causes and hospitalization for HF in patients with HFrEF, but the physiological mechanisms underlying these benefits are not fully understood. This single-arm, open-label, prospective study sought to test the hypothesis that short-term treatment with sacubitril-valsartan reduces SNS activity, measured directly via muscle sympathetic nerve activity (MSNA), in patients with HFrEF. MSNA, heart rate (HR), and arterial blood pressure (BP) were assessed in stable Class II and III patients with HFrEF (n = 9, 69 ± 8 yrs.; 28.6 ± 3.6 kg/m2) on contemporary, guideline-directed medical treatment who were subsequently started on sacubitril-valsartan. These measurements were repeated after two months of treatment with sacubitril-valsartan. Sacubitril-valsartan reduced MSNA burst frequency (baseline: 43 ± 10 bursts/min; 2-month: 36 ± 10 bursts/min, p = 0.05) and burst incidence (baseline: 68 ± 16 bursts/100 heartbeats; 2-month: 55 ± 16 bursts/100 heartbeats, p = 0.02), while HR and BP were unchanged following the treatment (p > 0.05). These preliminary findings provide new evidence regarding the ability of sacubitril-valsartan to rapidly reduce SNS activity in patients with HFrEF, suggesting the presence of a novel sympathoinhibitory effect of this new drug class.
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Insuficiencia Cardíaca , Aminobutiratos/uso terapéutico , Antagonistas de Receptores de Angiotensina/uso terapéutico , Compuestos de Bifenilo , Combinación de Medicamentos , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Proyectos Piloto , Estudios Prospectivos , Volumen Sistólico , Resultado del Tratamiento , ValsartánRESUMEN
The Prospective comparison of ARNI with angiotensin-converting enzyme inhibitor to Determine Impact on Global Mortality and morbidity in Heart Failure trial identified a marked reduction in the risk of death and hospitalization for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) treated with sacubitril-valsartan (trade name Entresto), but the physiological processes underpinning these improvements are unclear. We tested the hypothesis that treatment with sacubitril-valsartan improves peripheral vascular function, functional capacity, and inflammation in patients with HFrEF. We prospectively studied patients with HFrEF (n = 11, 10 M/1 F, left ventricular ejection fraction = 27 ± 8%) on optimal, guideline-directed medical treatment who were subsequently prescribed sacubitril-valsartan (open-label, uncontrolled, and unblinded). Peripheral vascular function [brachial artery flow-mediated dilation (FMD, conduit vessel function) and reactive hyperemia (RH, microvascular function)], functional capacity [six-minute walk test (6MWT) distance], and the proinflammatory biomarkers tumor necrosis factor-α (TNF-α) and interleukin-18 (IL-18) were obtained at baseline and at 1, 2, and 3 mo of treatment. %FMD improved after 1 mo of treatment, and this favorable response persisted for months 2 and 3 (baseline: 3.25 ± 1.75%; 1 mo: 5.23 ± 2.36%; 2 mo: 5.81 ± 1.79%; 3 mo: 6.35 ± 2.77%), whereas RH remained unchanged. 6MWT distance increased at months 2 and 3 (baseline: 420 ± 92 m; 1 mo: 436 ± 98 m; 2 mo: 465 ± 115 m; 3 mo: 460 ± 110 m), and there was a sustained reduction in TNF-α (baseline: 2.38 ± 1.35 pg/mL; 1 mo: 2.06 ± 1.52 pg/mL; 2 mo: 1.95 ± 1.34 pg/mL; 3 mo: 1.92 ± 1.37 pg/mL) and a reduction in IL-18 at month 3 (baseline: 654 ± 150 pg/mL; 1 mo: 595 ± 140 pg/mL; 2 mo: 601 ± 176 pg/mL; 3 mo: 571 ± 127 pg/mL). This study provides new evidence for the potential of this new drug class to improve conduit vessel function, functional capacity, and inflammation in patients with HFrEF.NEW & NOTEWORTHY We observed an approximately twofold improvement in conduit vessel function (brachial artery FMD), increased functional capacity (6MWT distance), and a reduction in inflammation (TNF-α and IL-18) following 3 mo of sacubitril-valsartan therapy. These findings provide important new information concerning the physiological mechanisms by which this new drug class provokes favorable changes in HFrEF pathophysiology.
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Insuficiencia Cardíaca , Aminobutiratos , Antagonistas de Receptores de Angiotensina , Compuestos de Bifenilo , Combinación de Medicamentos , Humanos , Inflamación , Estudios Prospectivos , Volumen Sistólico , Tetrazoles , Resultado del Tratamiento , Valsartán , Función Ventricular IzquierdaRESUMEN
Social recognition is fundamental for social decision making and the establishment of long-lasting affiliative behaviors in behaviorally complex social groups. It is a critical step in establishing a selective preference for a social partner or group member. C57BL/6J lab mice do not form monogamous relationships, and typically do not show prolonged social preferences for familiar mice. The CA2 hippocampal subfield plays a crucial role in social memory and optogenetic stimulation of inputs to the dorsal CA2 field during a short memory acquisition period can enhance and extend social memories in mice. Here, we show that partner preference in mice can be induced by chemogenetic selective stimulation of the monosynaptic projections from the hypothalamic paraventricular nucleus (PVN) to the CA2 during the cohabitation period. Specifically, male mice spend more time in social contact, grooming and huddling with the partner compared to a novel female. Preference was not induced by prolonging the cohabitation period and allowing more time for social interactions and males to sire pups with the familiar female. These results suggest that PVN-to-CA2 projections are part of an evolutionarily conserved neural circuitry underlying the formation of social preference and may promote behavioral changes with appropriate stimulation.
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Social interaction with unfamiliar individuals is necessary for species-preserving behaviors such as finding mates and establishing social groups. However, social conflict is a potential negative outcome to interaction with a stranger that can be distressing enough to cause an individual to later avoid interactions with other unfamiliar conspecifics. Unfortunately, stress research using a prominent model of social conflict, social defeat stress, has largely omitted female subjects. This has left a void in the literature regarding social strain on female stress biology and adequate comparison of the effect of sex in stress pathways. The prairie vole (Microtus ochrogaster) exhibits aggressive behavior in both sexes, making voles an attractive candidate to model social defeat in both sexes. This study sought to establish a model of social defeat stress in both male and female prairie voles, characterize behavioral changes in response to this stressor, and investigate the role of dopamine signaling in the response to social defeat stress. Defeated male and female prairie voles displayed social avoidance as well as an increase in the level of dopamine receptor D1 (DRD1) in the medial amygdala (MeA). Pharmacological manipulation of DRD1 signaling in the MeA revealed that increased DRD1 signaling is sufficient to induce a social avoidant state, and could be a necessary component in the defeat-induced social avoidance response. These findings provide the prairie vole as a model of social defeat in both sexes, and implicate the MeA in avoidance of unfamiliar conspecifics after a distressing social encounter.
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Complejo Nuclear Corticomedial/metabolismo , Receptores de Dopamina D1/metabolismo , Estrés Psicológico/metabolismo , Amígdala del Cerebelo/metabolismo , Animales , Arvicolinae , Conducta Animal/fisiología , Femenino , Masculino , Receptores de Dopamina D1/fisiología , Conducta Social , Derrota Social , Estrés Psicológico/fisiopatologíaRESUMEN
Agouti-related peptide (AgRP) neurons of the hypothalamus play a role in hunger-triggered food intake, stability of body weight, and long-term energy balance. A recent study showed that activation of the Gs-linked G protein-coupled receptors (GCPR) expressed by hypothalamic AgRP neurons promotes a sustained increase in food intake. Enhanced AgRP release has been the postulated underlying mechanism. Here, we confirmed that activation of Gs-coupled receptors expressed by AgRP neurons in the arcuate nucleus (ARC) of the hypothalamus, which is the primary brain region for the synthesis and release of AgRP, leads to increased release of AgRP in the paraventricular nucleus of the hypothalamus (PVN). We were unable to confirm changes in AgRP expression or intracellular content using traditional histological techniques. Thus, we developed an assay to measure AgRP in the extracellular fluid in the brain using large molecular weight cut-off microdialysis probes. Our technique enables assessment of brain AgRP pharmacokinetics under physiological conditions and in response to specific pharmacological interventions designed to modulate AgRP signaling.
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Intranasal delivery of oxytocin (Oxt) has been identified as a potential therapeutic to target human conditions characterized by social deficits, yet the ability of this administrative route to deliver to the brain is unconfirmed. Oxt knockout (Oxt KO) and wildtype C57BL/6â¯J male mice received Oxt (12⯵g total amount) either by nasal or intraperitoneal administration. Oxt concentrations were monitored for 2â¯h after administration in circulation via a jugular vein catheter and in the brain by two intracerebral microdialysis probes. Group sizes varied from 4 to 7 mice (nâ¯=â¯22 total). We document for the first time that Oxt applied to the nasal mucosa after nasal administration is delivered to the extracellular fluid in the brain. After nasal application, Oxt concentrations in circulation and in the extracellular fluid of the amygdala and, to an extent, the dorsal hippocampus, rose within the first 30â¯min and remained elevated for the subsequent hour. These findings were confirmed in an Oxt KO mouse line, establishing that the circulating and brain Oxt elevations derive from the administered dose. Interestingly, the pharmacokinetics of Oxt were slightly biased to the brain after nasal administration and to the periphery following intraperitoneal injection. No change in vasopressin levels was detected. These findings have stimulating implications for the interpretation of various behavioral and physiological effects described in animal and human studies after nasal administration of Oxt and provide the pharmacokinetics necessary to develop this drug delivery route for therapeutic purposes.
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Amígdala del Cerebelo/metabolismo , Hipocampo/metabolismo , Oxitocina/administración & dosificación , Administración Intranasal , Amígdala del Cerebelo/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Inyecciones Intraperitoneales/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microdiálisis/métodos , Oxitocina/sangre , Oxitocina/metabolismo , Vasopresinas/sangre , Vasopresinas/metabolismoRESUMEN
The prairie vole (Microtus ochrogaster) is a socially monogamous rodent species that forms a lasting connection between mates, known as a pair bond. The pair bond is primarily characterized by three distinct behaviors: partner preference, selective aggression, and biparental care of the young. The presence of these behaviors in the prairie vole and their absence in closely related non-monogamous species makes the prairie vole an important model of social relationships and facilitates the study of the neurobiological mechanisms of social affiliation and attachment. The nona-peptide arginine-vasopressin (AVP) is an important neuromodulator of social behavior and has been implicated in the regulation of the pair bond-related behaviors of the prairie vole, through activation of the AVP receptor subtype 1a (AVPR1a). Modulation of AVPR1a activity in different regions of the prairie vole brain impacts pair bond behavior, suggesting a role of AVP in neurocircuitry responsible for the regulation of social attachment. This review will discuss findings that have suggested the role of AVP in regulation of the pair bond-related behaviors of the prairie vole and the specific brain regions through which AVP acts to impact these unique behaviors.
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Agouti-related peptide (AgRP) neurons of the hypothalamus play a key role in regulating food intake and body weight, by releasing three different orexigenic molecules: AgRP; GABA; and neuropeptide Y. AgRP neurons express various G protein-coupled receptors (GPCRs) with different coupling properties, including Gs-linked GPCRs. At present, the potential role of Gs-coupled GPCRs in regulating the activity of AgRP neurons remains unknown. Here we show that the activation of Gs-coupled receptors expressed by AgRP neurons leads to a robust and sustained increase in food intake. We also provide detailed mechanistic data linking the stimulation of this class of receptors to the observed feeding phenotype. Moreover, we show that this pathway is clearly distinct from other GPCR signalling cascades that are operative in AgRP neurons. Our data suggest that drugs able to inhibit this signalling pathway may become useful for the treatment of obesity.
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Proteína Relacionada con Agouti/genética , Ingestión de Alimentos/genética , Hipotálamo/metabolismo , Neuronas/metabolismo , Neuropéptido Y/genética , ARN Mensajero/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Proteína Relacionada con Agouti/metabolismo , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Células HEK293 , Humanos , Hipotálamo/citología , Inmunohistoquímica , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , Neuropéptido Y/metabolismo , Técnicas de Placa-Clamp , Fosfoproteínas , Proteínas Proto-Oncogénicas c-fos/metabolismo , Transducción de Señal , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Oxytocin (Oxt) is released in various hypothalamic and extrahypothalamic brain areas in response to anxiogenic stimuli to regulate aspects of emotionality and stress coping. We examined the anxiolytic action of Oxt in the hypothalamic paraventricular nucleus (PVN) while appraising if Oxt recruits GABA neurons to inhibit the behavioral, hormonal, and neuronal response to stress in female prairie voles (Microtus ochrogaster). Voles received an injection of Oxt in the PVN either before or after an elevated platform stress to determine a time-course for the effects of Oxt on the hormonal stress response. Subsequently, we evaluated if ante-stress injections of Oxt affected anxiety-like behaviors as well as neuronal activity in the PVN, using real-time in-vivo retrodialysis and immunohistochemistry with c-Fos expression as a biomarker of neural activity. In addition, we exposed voles to Oxt and a GABAA receptor antagonist, concurrently, to evaluate the impact of pharmacological blockade of GABAA receptors on the anxiolytic effects of Oxt. Elevated platform stress amplified anxiety-like behaviors and hypothalamic-pituitary-adrenal (HPA) axis activity-catalyzing corticotrophin-releasing hormone (CRH) neuronal activity and augmenting corticosterone release in circulation. Ante-stress Oxt injections in the PVN blocked these stress effects while promoting PVN GABA activity and release. Post-stress Oxt treatments were ineffective. The anxiolytic effects of Oxt were hindered by concurrent pharmacological blockade of GABAA receptors. Together, our data demonstrate ante-stress treatments of Oxt in the PVN inhibit stress activation of the HPA axis through recruitment of GABAergic neurons, providing insights to the local circuitry and potential therapeutically-relevant mechanisms.