RESUMEN
Cholinergic interneurons (ChIs) provide the main source of acetylcholine in the striatum and have emerged as a critical modulator of behavioral flexibility, motivation, and associative learning. In the dorsal striatum (DS), ChIs display heterogeneous firing patterns. Here, we investigated the spontaneous firing patterns of ChIs in the nucleus accumbens (NAc) shell, a region of the ventral striatum. We identified four distinct ChI firing signatures: regular single-spiking, irregular single-spiking, rhythmic bursting, and a mixed-mode pattern composed of bursting activity and regular single spiking. ChIs from females had lower firing rates compared with males and had both a higher proportion of mixed-mode firing patterns and a lower proportion of regular single-spiking neurons compared with males. We further observed that across the estrous cycle, the diestrus phase was characterized by higher proportions of irregular ChI firing patterns compared with other phases. Using pooled data from males and females, we examined how the stress-associated neuropeptide corticotropin releasing factor (CRF) impacts these firing patterns. ChI firing patterns showed differential sensitivity to CRF. This translated into differential ChI sensitivity to CRF across the estrous cycle. Furthermore, CRF shifted the proportion of ChI firing patterns toward more regular spiking activity over bursting patterns. Finally, we found that repeated stressor exposure altered ChI firing patterns and sensitivity to CRF in the NAc core, but not the NAc shell. These findings highlight the heterogeneous nature of ChI firing patterns, which may have implications for accumbal-dependent motivated behaviors.NEW & NOTEWORTHY Cholinergic interneurons (ChIs) within the dorsal and ventral striatum can exert a major influence on network output and motivated behaviors. However, the firing patterns and neuromodulation of ChIs within the ventral striatum, specifically the nucleus accumbens (NAc) shell, are understudied. Here, we report that NAc shell ChIs have heterogeneous ChI firing patterns that are labile and can be modulated by the stress-linked neuropeptide corticotropin releasing factor (CRF) and by the estrous cycle.
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Neuronas Colinérgicas , Hormona Liberadora de Corticotropina , Interneuronas , Núcleo Accumbens , Animales , Hormona Liberadora de Corticotropina/metabolismo , Hormona Liberadora de Corticotropina/farmacología , Femenino , Masculino , Interneuronas/fisiología , Interneuronas/metabolismo , Núcleo Accumbens/fisiología , Núcleo Accumbens/metabolismo , Núcleo Accumbens/citología , Neuronas Colinérgicas/fisiología , Neuronas Colinérgicas/metabolismo , Ciclo Estral/fisiología , Potenciales de Acción/fisiología , RatonesRESUMEN
Nicotine intake is linked to the maintenance and development of anxiety disorders and impairs adaptive discrimination of threat and safety in rodents and humans. Yet, it is unclear if nicotine exerts a causal pharmacological effect on the affective and neural mechanisms that underlie aversive learning. We conducted a pre-registered, pseudo-randomly and double-blinded pharmacological fMRI study to investigate the effect of acute nicotine on Fear Acquisition and Extinction in non-smokers (n = 88). Our results show that nicotine administration led to decreased discrimination between threat and safety in subjective fear. Nicotine furthermore decreased differential (threat vs. safety) activation in the hippocampus, which was functionally coupled with Nucleus Accumbens and amygdala, compared to placebo controls. Additionally, nicotine led to enhanced physiological arousal to learned threats and overactivation of the ventral tegmental area. This study provides mechanistic evidence that single doses of nicotine impair neural substrates of adaptive aversive learning in line with the risk for the development of pathological anxiety.
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Amígdala del Cerebelo , Miedo , Hipocampo , Imagen por Resonancia Magnética , Nicotina , Núcleo Accumbens , Humanos , Nicotina/farmacología , Nicotina/efectos adversos , Nicotina/administración & dosificación , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/diagnóstico por imagen , Masculino , Hipocampo/efectos de los fármacos , Miedo/efectos de los fármacos , Adulto , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/diagnóstico por imagen , Femenino , Adulto Joven , Método Doble Ciego , Discriminación en Psicología/efectos de los fármacos , Agonistas Nicotínicos/farmacología , Agonistas Nicotínicos/efectos adversos , Agonistas Nicotínicos/administración & dosificación , Extinción Psicológica/efectos de los fármacosRESUMEN
Powerful associations that link drugs of abuse with cues in the drug-paired environment often serve as prepotent relapse triggers. Drug-associated contexts and cues activate ensembles of nucleus accumbens (NAc) neurons, including D1-class medium spiny neurons (MSNs) that typically promote, and D2-class MSNs that typically oppose, drug seeking. We found that in mice, cocaine conditioning upregulated transiently the activity-regulated transcription factor, Neuronal PAS Domain Protein 4 (NPAS4), in a small subset of NAc neurons. The NPAS4+ NAc ensemble was required for cocaine conditioned place preference. We also observed that NPAS4 functions within NAc D2-, but not D1-, MSNs to support cocaine-context associations and cue-induced cocaine, but not sucrose, seeking. Together, our data show that the NPAS4+ ensemble of NAc neurons is essential for cocaine-context associations in mice, and that NPAS4 itself functions in NAc D2-MSNs to support cocaine-context associations by suppressing drug-induced counteradaptations that oppose relapse-related behaviour.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Cocaína , Señales (Psicología) , Neuronas , Núcleo Accumbens , Animales , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efectos de los fármacos , Cocaína/farmacología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Ratones , Masculino , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Ratones Endogámicos C57BL , Comportamiento de Búsqueda de Drogas , Receptores de Dopamina D2/metabolismoRESUMEN
Neural processing of rewarding stimuli involves several distinct regions, including the nucleus accumbens (NAc). The majority of NAc neurons are GABAergic projection neurons known as medium spiny neurons (MSNs). MSNs are broadly defined by dopamine receptor expression, but evidence suggests that a wider array of subtypes exist. To study MSN heterogeneity, we analyzed single-nucleus RNA sequencing data from the largest available rat NAc dataset. Analysis of 48,040 NAc MSN nuclei identified major populations belonging to the striosome and matrix compartments. Integration with mouse and human data indicated consistency across species and disease-relevance scoring using genome-wide association study results revealed potentially differential roles for MSN populations in substance use disorders. Additional high-resolution clustering identified 34 transcriptomically distinct subtypes of MSNs definable by a limited number of marker genes. Together, these data demonstrate the diversity of MSNs in the NAc and provide a basis for more targeted genetic manipulation of specific populations.
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Núcleo Accumbens , Transcriptoma , Animales , Humanos , Ratones , Ratas , Núcleo Celular/metabolismo , Núcleo Celular/genética , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Neuronas Espinosas Medianas/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Accumbens/citología , Análisis de la Célula IndividualRESUMEN
Clinical evidence suggests that early malnutrition promotes symptoms related to psychiatric disorders later in life. Nevertheless, the molecular mechanisms underpinning nutritional injury induce depression remains unknown. The purpose of the present study was to evaluate whether perinatal protein restriction increases vulnerability to developing depressive-like behavior in adulthood by focusing on anhedonia, a core symptom of depression. To this, male adult Wistar rats submitted to a protein restriction schedule at perinatal age (PR-rats), were subjected to the sucrose preference test (SPT), the novel object recognition test (NORT), the forced swim test (FST), and the elevated plus maze (EPM), and compared to animals fed with a normoprotein diet. To investigate neurobiological substrates linked to early protein undernutrition-facilitated depressive-like behavior, we assessed the levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the nucleus accumbens (NAc), and evaluated the reversal of anhedonic-like behavior by infusing ANA-12. We found that early malnutrition decreased sucrose preference, impaired performance in the NORT and increased immobility time in the FST. Furthermore, perinatal protein-restriction-induced anhedonia correlated with increased BDNF and p-TrkB protein levels in the NAc, a core structure in the reward circuit linked with anhedonia. Finally, bilateral infusion of the TrkB antagonist ANA-12 into the NAc shell ameliorated a reduced sucrose preference in the PR-rats. Altogether, these findings revealed that protein restriction during pregnancy and lactation facilitates depressive-like behavior later in life and may increase the risk of developing anhedonia by altering BDNF-TrkB in the NAc shell.
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Anhedonia , Factor Neurotrófico Derivado del Encéfalo , Núcleo Accumbens , Ratas Wistar , Receptor trkB , Transducción de Señal , Animales , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Masculino , Anhedonia/fisiología , Ratas , Receptor trkB/metabolismo , Femenino , Transducción de Señal/fisiología , Transducción de Señal/efectos de los fármacos , Embarazo , Dieta con Restricción de Proteínas , Efectos Tardíos de la Exposición Prenatal/metabolismo , Depresión/metabolismo , Depresión/psicología , Azepinas , BenzamidasRESUMEN
Whilst reward pathologies are major and common in stress-related neuropsychiatric disorders, their neurobiology and treatment are poorly understood. Imaging studies in human reward pathology indicate attenuated BOLD activity in nucleus accumbens (NAc) coincident with reward anticipation but not reinforcement; potentially, this is dopamine (DA) related. In mice, chronic social stress (CSS) leads to reduced reward learning and motivation. Here, DA-sensor fibre photometry is used to investigate whether these behavioural deficits co-occur with altered NAc DA activity during reward anticipation and/or reinforcement. In CSS mice relative to controls: (1) Reduced discriminative learning of the sequence, tone-on + appetitive behaviour = tone-on + sucrose reinforcement, co-occurs with attenuated NAc DA activity throughout tone-on and sucrose reinforcement. (2) Reduced motivation during the sequence, operant behaviour = tone-on + sucrose delivery + sucrose reinforcement, co-occurs with attenuated NAc DA activity at tone-on and typical activity at sucrose reinforcement. (3) Reduced motivation during the sequence, operant behaviour = appetitive behaviour + sociosexual reinforcement, co-occurs with typical NAc DA activity at female reinforcement. Therefore, in CSS mice, low NAc DA activity co-occurs with low reward anticipation and could account for deficits in learning and motivation, with important implications for understanding human reward pathology.
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Dopamina , Núcleo Accumbens , Recompensa , Estrés Psicológico , Núcleo Accumbens/metabolismo , Animales , Dopamina/metabolismo , Ratones , Masculino , Estrés Psicológico/metabolismo , Femenino , Ratones Endogámicos C57BL , Motivación , Anticipación Psicológica , Conducta Animal , Refuerzo en PsicologíaRESUMEN
BACKGROUND: Anxiety disorders are one of the most common mental disorders. Ghrelin is a critical orexigenic brain-gut peptide that regulates food intake and metabolism. Recently, the ghrelin system has attracted more attention for its crucial roles in psychiatric disorders, including depression and anxiety. However, the underlying neural mechanisms involved have not been fully investigated. METHODS: In the present study, the effect and underlying mechanism of ghrelin signaling in the nucleus accumbens (NAc) core on anxiety-like behaviors were examined in normal and acute stress rats, by using immunofluorescence, qRT-PCR, neuropharmacology, molecular manipulation and behavioral tests. RESULTS: We reported that injection of ghrelin into the NAc core caused significant anxiolytic effects. Ghrelin receptor growth hormone secretagogue receptor (GHSR) is highly localized and expressed in the NAc core neurons. Antagonism of GHSR blocked the ghrelin-induced anxiolytic effects. Moreover, molecular knockdown of GHSR induced anxiogenic effects. Furthermore, injection of ghrelin or overexpression of GHSR in the NAc core reduced acute restraint stress-induced anxiogenic effects. CONCLUSIONS: This study demonstrates that ghrelin and its receptor GHSR in the NAc core are actively involved in modulating anxiety induced by acute stress, and raises an opportunity to treat anxiety disorders by targeting ghrelin signaling system.
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Ansiedad , Ghrelina , Núcleo Accumbens , Ratas Sprague-Dawley , Receptores de Ghrelina , Transducción de Señal , Estrés Psicológico , Animales , Ghrelina/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efectos de los fármacos , Masculino , Ansiedad/metabolismo , Ansiedad/psicología , Receptores de Ghrelina/metabolismo , Receptores de Ghrelina/genética , Ratas , Estrés Psicológico/metabolismo , Estrés Psicológico/psicología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Conducta Animal/efectos de los fármacosRESUMEN
Some mental health problems such as depression and anxiety are more common in females, while others such as autism and attention deficit/hyperactivity (AD/H) are more common in males. However, the neurobiological origins of these sex differences are poorly understood. Animal studies have shown substantial sex differences in neuronal and glial cell structure, while human brain imaging studies have shown only small differences, which largely reflect overall body and brain size. Advanced diffusion MRI techniques can be used to examine intracellular, extracellular, and free water signal contributions and provide unique insights into microscopic cellular structure. However, the extent to which sex differences exist in these metrics of subcortical gray matter structures implicated in psychiatric disorders is not known. Here, we show large sex-related differences in microstructure in subcortical regions, including the hippocampus, thalamus, and nucleus accumbens in a large sample of young adults. Unlike conventional T1-weighted structural imaging, large sex differences remained after adjustment for age and brain volume. Further, diffusion metrics in the thalamus and amygdala were associated with depression, anxiety, AD/H, and antisocial personality problems. Diffusion MRI may provide mechanistic insights into the origin of sex differences in behavior and mental health over the life course and help to bridge the gap between findings from experimental, epidemiological, and clinical mental health research.
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Encéfalo , Caracteres Sexuales , Humanos , Femenino , Masculino , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Salud Mental , Adulto Joven , Imagen de Difusión por Resonancia Magnética , Adolescente , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Tálamo/diagnóstico por imagen , Núcleo Accumbens/diagnóstico por imagen , Depresión/diagnóstico por imagen , Depresión/patología , Ansiedad/diagnóstico por imagenRESUMEN
The mechanisms contributing to alcohol use disorder (AUD) are complex and the orexigenic peptide ghrelin, which enhances alcohol reward, is implied as a crucial modulator. The major proportion of circulating ghrelin is however the non-octanoylated form of ghrelin, des-acyl ghrelin (DAG), whose role in reward processes is unknown. As recent studies show that DAG decreases food intake, we hypothesize that DAG attenuates alcohol-related responses in animal models. Acute and repeated DAG treatment dose-dependently decreased alcohol drinking in male and female rats. In these alcohol-consuming male rats, repeated DAG treatment causes higher levels of dopamine metabolites in the ventral tegmental area, an area central to reward processing. The role of DAG in reward processing is further supported as DAG prevents alcohol-induced locomotor stimulation, reward in the conditioned place preference paradigm, and dopamine release in the nucleus accumbens in male rodents. On the contrary, DAG does not alter the memory of alcohol reward or affect neurotransmission in the hippocampus, an area central to memory. Further, circulating DAG levels are positively correlated with alcohol drinking in female but not male rats. Studies were conducted in attempts to identify tentative targets of DAG, which currently are unknown. Data from these recombinant cell system revealed that DAG does not bind to either of the monoamine transporters, 5HT2A, CB1, or µ-opioid receptors. Collectively, our data show that DAG attenuates alcohol-related responses in rodents, an effect opposite to that of ghrelin, and contributes towards a deeper insight into behaviors regulated by the ghrelinergic signaling pathway.
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Consumo de Bebidas Alcohólicas , Dopamina , Ghrelina , Núcleo Accumbens , Recompensa , Área Tegmental Ventral , Animales , Ghrelina/farmacología , Ghrelina/metabolismo , Masculino , Ratas , Femenino , Dopamina/metabolismo , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efectos de los fármacos , Etanol/farmacología , Etanol/administración & dosificación , Humanos , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratas Sprague-DawleyRESUMEN
It is well established that the basolateral amygdala (BLA) is an emotional processing hub that governs a diverse repertoire of behaviors. Selective engagement of a heterogeneous cell population in the BLA is thought to contribute to this flexibility in behavioral outcomes. However, whether this process is impacted by previous experiences that influence emotional processing remains unclear. Here we demonstrate that previous positive (enriched environment [EE]) or negative (chronic unpredictable stress [CUS]) experiences differentially influence the activity of populations of BLA principal neurons projecting to either the nucleus accumbens core or bed nucleus of the stria terminalis. Chemogenetic manipulation of these projection-specific neurons can mimic or occlude the effects of CUS and EE on behavioral outcomes to bidirectionally control avoidance behaviors and stress-induced helplessness. These data demonstrate that previous experiences influence the responsiveness of projection-specific BLA principal neurons, biasing information routing through the BLA, to drive divergent behavioral outcomes.
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Complejo Nuclear Basolateral , Conducta Animal , Animales , Complejo Nuclear Basolateral/fisiología , Masculino , Neuronas/fisiología , Ratones , Estrés Psicológico , Núcleo Accumbens/fisiología , Ratones Endogámicos C57BL , Núcleos Septales/fisiologíaRESUMEN
Electronic cigarettes (e-cigs) use, especially among youngsters, has been on the rise in recent years. However, little is known about the long-term effects of the use of e-cigs on brain functional activity. We acquired the resting-state functional magnetic resonance imaging (rs-fMRI) data from 93 e-cigs users with nicotine dependence and 103 health controls (HC). The local synchronization was analyzed via the regional homogeneity (ReHo) method at voxel-wise level. The functional connectivity (FC) between the nucleus accumbens (NAcc), the ventral tegmental area (VTA), and the insula was calculated at ROI-wise level. The support vector machining classification model based on rs-fMRI measures was used to identify e-cigs users from HC. Compared with HC, nicotine-dependent e-cigs users showed increased ReHo in the right rolandic operculum and the right insula (p < 0.05, FDR corrected). At the ROI-wise level, abnormal FCs between the NAcc, the VTA, and the insula were found in e-cigs users compared to HC (p < 0.05, FDR corrected). Correlation analysis found a significant negative correlation between ReHo in the left NAcc and duration of e-cigs use (r = -0.273, p = 0.008, FDR corrected). The following support vector machine model based on significant results of rs-fMRI successfully differentiates chronic e-cigs users from HC with an accuracy of 73.47%, an AUC of 0.781, a sensitivity of 67.74%, and a specificity of 78.64%. Dysregulated spontaneous activity and FC of addiction-related regions were found in e-cigs users with nicotine dependence, which provides crucial insights into the prevention of its initial use and intervention for quitting e-cigs.
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Sistemas Electrónicos de Liberación de Nicotina , Imagen por Resonancia Magnética , Núcleo Accumbens , Tabaquismo , Humanos , Tabaquismo/fisiopatología , Tabaquismo/diagnóstico por imagen , Masculino , Femenino , Adulto , Núcleo Accumbens/diagnóstico por imagen , Núcleo Accumbens/fisiopatología , Adulto Joven , Corteza Insular/diagnóstico por imagen , Corteza Insular/fisiopatología , Área Tegmental Ventral/diagnóstico por imagen , Área Tegmental Ventral/fisiopatología , Máquina de Vectores de Soporte , Estudios de Casos y Controles , Vapeo/fisiopatologíaRESUMEN
Electrical brain stimulation has been used in vivo and in vitro to investigate neural circuitry. Historically, stimulation parameters such as amplitude, frequency, and pulse width were varied to investigate their effects on neurotransmitter release and behavior. These experiments have traditionally employed fixed-frequency stimulation patterns, but it has previously been found that neurons are more precisely tuned to variable input. Introducing variability into the interpulse interval of stimulation pulses will inform on how dopaminergic release can be modulated by variability in pulse timing. Here, dopaminergic release in rats is monitored in the nucleus accumbens (NAc), a key dopaminergic center which plays a role in learning and motivation, by fast-scan cyclic voltammetry. Dopaminergic release in the NAc could also be modulated by stimulation region due to differences in connectivity. We targeted two regions for stimulationâthe medial forebrain bundle (MFB) and the medial prefrontal cortex (mPFC)âdue to their involvement in reward processing and projections to the NAc. Our goal is to investigate how variable interpulse interval stimulation patterns delivered to these regions affect the time course of dopamine release in the NAc. We found that stimulating the MFB with these variable stimulation patterns saw a highly responsive, frequency-driven dopaminergic response. In contrast, variable stimulation patterns applied to the mPFC were not as sensitive to the variable frequency changes. This work will help inform on how stimulation patterns can be tuned specifically to the stimulation region to improve the efficiency of electrical stimulation and control dopamine release.
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Dopamina , Estimulación Eléctrica , Haz Prosencefálico Medial , Núcleo Accumbens , Corteza Prefrontal , Ratas Sprague-Dawley , Animales , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiología , Dopamina/metabolismo , Corteza Prefrontal/fisiología , Corteza Prefrontal/metabolismo , Haz Prosencefálico Medial/fisiología , Masculino , Estimulación Eléctrica/métodos , Ratas , Factores de TiempoRESUMEN
BACKGROUND: The transition from childhood to adulthood, or adolescence, a developmental stage, is characterized by psychosocial and biological changes. The nucleus accumbens (NAc), a striatal brain region composed of the core (NAcC) and shell (NAcSh), has been linked to risk-taking behavior and implicated in reward seeking and evaluation. Most neurons in the NAc are medium spiny neurons (MSNs) that express dopamine D1 receptors (D1R +) and/or dopamine D2 receptors (D2R +). Changes in dopaminergic and glutamatergic systems occur during adolescence and converge in the NAc. While there are previous investigations into sex differences in membrane excitability and synaptic glutamate transmission in both subdivisions of the NAc, to our knowledge, none have specified NAcSh D1R + MSNs from mice during pre- and mid-adolescence. METHODS: Sagittal brain slices containing the NAc were prepared from B6.Cg-Tg(Drd1a-tdTomato)6Calak/J mice of both sexes from postnatal days 21-25 and 35-47, representing pre- and mid-adolescence, respectively. Whole-cell electrophysiology recordings were collected from NAcSh D1R + MSNs in the form of membrane-voltage responses to current injections, to assess membrane properties and action potential waveform characteristics, and spontaneous excitatory postsynaptic currents (sEPSCs) to assess glutamatergic synaptic activity. RESULTS: Relative to pre-adolescent males, pre-adolescent female NAcSh D1R + MSNs exhibited a less hyperpolarized resting membrane potential, increased input resistance, and smaller action potential afterhyperpolarization amplitudes. During mid-adolescence, decreased input resistance and a shorter action potential duration in females were the only sex differences observed. CONCLUSIONS: Taken together, our results indicate that NAcSh D1R + MSNs in mice exhibit sex differences in membrane properties and AP waveform during pre-adolescence that are overall indicative of increased cellular excitability in females and are suggestive of possible sex differences in glycine receptors, inwardly-rectifying potassium channels, and large conductance voltage-gated potassium channels. These differences do not appear to persist into mid-adolescence, when sex was observed to affect input resistance oppositely to that of pre-adolescence and AP waveform in a manner suggestive of differences in voltage-gated potassium channels.
Adolescence marks a period of substantial changes in both the mind and body, where alterations in the brain's structure can influence behavior. One change in behavior exhibited by many adolescents is an increased tendency to take risks, particularly in males. While taking risks can result in positive outcomes, like learning new skills, it can also lead to reckless behaviors that may result in negative outcomes. The nucleus accumbens, a brain region tied to risk-taking and reward perception, is not well-studied during the transition from childhood to adulthood, particularly in terms of sex differences. To fill this gap in understanding, this study examined a specific type of brain cell in the nucleus accumbens of pre- and mid-adolescent male and female mice. We measured the electrical properties of these cells and assessed how they responded to manipulation of their electrical state. We also measured how much and how often excitatory electrical information is sent to these cells from other brain regions. Our results suggest that in pre-adolescent females, these brain cells are more excited by manipulations of their electrical state and that these brain cells in mid-adolescent males may take longer to communicate information to other brain regions than in similarly aged females. Understanding these intricacies of brain cell communication sheds light on potential sex-specific vulnerabilities during the transition from childhood to adulthood.
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Neuronas , Núcleo Accumbens , Receptores de Dopamina D1 , Caracteres Sexuales , Animales , Receptores de Dopamina D1/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiología , Núcleo Accumbens/citología , Femenino , Masculino , Neuronas/metabolismo , Neuronas/fisiología , Ratones , Potenciales de la Membrana , Ratones Endogámicos C57BL , Potenciales Postsinápticos Excitadores , Ratones TransgénicosRESUMEN
Sleep disturbances and persistent pain conditions are public health challenges worldwide. Although it is well-known that sleep deficit increases pain sensitivity, the underlying mechanisms remain elusive. We have recently demonstrated the involvement of nucleus accumbens (NAc) and anterior cingulate cortex (ACC) in the pronociceptive effect of sleep restriction. In this study, we found that sleep restriction increases c-Fos expression in NAc and ACC, suggesting hyperactivation of these regions during prolonged wakefulness in male Wistar rats. Blocking adenosine A2A receptors in the NAc or GABAA receptors in the ventral tegmental area (VTA), dorsal raphe nucleus (DRN), or locus coeruleus (LC) effectively mitigated the pronociceptive effect of sleep restriction. In contrast, the blockade of GABAA receptors in each of these nuclei only transiently reduced carrageenan-induced hyperalgesia. Pharmacological activation of dopamine D2, serotonin 5-HT1A and noradrenaline alpha-2 receptors within the ACC also prevented the pronociceptive effect of sleep restriction. While pharmacological inhibition of these same monoaminergic receptors in the ACC restored the pronociceptive effect which had been prevented by the GABAergic disinhibition of the of the VTA, DRN or LC. Overall, these findings suggest that the pronociceptive effect of sleep restriction relies on increased adenosinergic activity on NAc, heightened GABAergic activity in VTA, DRN, and LC, and reduced inhibitory monoaminergic activity on ACC. These findings advance our understanding of the interplay between sleep and pain, shedding light on potential NAc-brainstem-ACC mechanisms that could mediate increased pain sensitivity under conditions of sleep impairment.
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Núcleo Accumbens , Ratas Wistar , Privación de Sueño , Área Tegmental Ventral , Animales , Masculino , Privación de Sueño/metabolismo , Privación de Sueño/fisiopatología , Ratas , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efectos de los fármacos , Receptor de Adenosina A2A/metabolismo , Hiperalgesia/metabolismo , Núcleo Dorsal del Rafe/metabolismo , Núcleo Dorsal del Rafe/efectos de los fármacos , Giro del Cíngulo/metabolismo , Giro del Cíngulo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Tronco Encefálico/metabolismo , Tronco Encefálico/efectos de los fármacos , Locus Coeruleus/metabolismo , Locus Coeruleus/efectos de los fármacos , Carragenina , Receptores de GABA-A/metabolismo , Receptores de Dopamina D2/metabolismo , Antagonistas del Receptor de Adenosina A2/farmacologíaRESUMEN
The complicated relevance between stress and pain has been identified. Neurotransmitters and neuropeptides of various brain areas play a role in this communication. Pain inhibitory response is known as stress-induced analgesia (SIA). The studies demonstrated that the nucleus accumbens (NAc) is critical in modulating pain. As a neuropeptide, orexin is crucially involved in initiating behavioral and physiological responses to threatening and unfeeling stimuli. However, the role of the orexin receptors of the NAc area after exposure to restraint stress (RS) as acute physical stress in the modulation of acute pain is unclear. One hundered twenty adult male albino Wistar rats (230-250â¯g) were used. Animals were unilaterally implanted with cannulae above the NAc. The SB334867 and TCS OX2 29 were used as antagonists for OX1r and OX2r, respectively. Different doses of the antagonists (1, 3, 10, and 30 nmol/0.5⯵l DMSO) were microinjected intra-NAc five minutes before exposure to RS (3â¯hours). Then, the tail-flick test as a model of acute pain was performed, and the nociceptive threshold (Tail-flick latency; TFL) was measured in 60-minute time set intervals. According to this study's findings, the antinociceptive effects of RS in the tail-flick test were blocked during intra-NAc administration of SB334867 or TCS OX2 29. The RS as acute stress increased TFL and deceased pain-like behavior responses. The 50â¯% effective dose values of the OX1r and OX2r antagonists were 12.82 and 21.64 nmol, respectively. The result demonstrated contribution of the OX1r into the NAc was more remarkable than that of the OX2r on antinociceptive responses induced by the RS. Besides, in the absence of RS, the TFL was attenuated. The current study's data indicated that OX1r and OX2r into the NAc induced pain modulation responses during RS in acute pain. In conclusion, the findings revealed the involvement of intra-NAc orexin receptors in improving SIA.
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Dolor Agudo , Benzoxazoles , Naftiridinas , Núcleo Accumbens , Antagonistas de los Receptores de Orexina , Receptores de Orexina , Ratas Wistar , Restricción Física , Estrés Psicológico , Urea , Animales , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Masculino , Receptores de Orexina/metabolismo , Benzoxazoles/farmacología , Antagonistas de los Receptores de Orexina/farmacología , Antagonistas de los Receptores de Orexina/administración & dosificación , Urea/análogos & derivados , Urea/farmacología , Urea/administración & dosificación , Dolor Agudo/fisiopatología , Dolor Agudo/tratamiento farmacológico , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Naftiridinas/farmacología , Isoquinolinas/farmacología , Isoquinolinas/administración & dosificación , Ratas , Piridinas/farmacología , Piridinas/administración & dosificación , Orexinas/farmacología , Orexinas/metabolismo , Relación Dosis-Respuesta a Droga , Dimensión del Dolor/efectos de los fármacos , Aminopiridinas , SulfonamidasRESUMEN
Clavulanic acid (CLAV) is a component of Augmentin® that preserves antibiotic efficacy by inhibiting ß-lactamase activity. It also enhances cellular glutamate uptake and is a potential CNS therapeutic. Because increased glutamate transmission in brain reward circuits facilitates methamphetamine (METH) locomotor activation and sensitization, we tested the hypothesis that CLAV inhibits acute and sensitized locomotor responses to METH in mice and investigated effects of CLAV on METH-induced changes in glutaminase, the major glutamate-producing enzyme in the brain. Acute METH (3 mg/kg) produced hyperlocomotion that was reduced by CLAV (20 mg/kg but not 10 mg/kg). Mice injected with METH (3 mg/kg) every other day for 9 d and then challenged with METH 27 d later displayed locomotor sensitization. CLAV (10 mg/kg), when injected 15 min before each METH injection during the 9-d exposure interval, blocked locomotor sensitization induced by METH challenge. In METH-sensitized mice, mRNA levels of both isoforms of glutaminase (GLS and GLS2) were altered in the nucleus accumbens compared to mice exposed to a single injection of METH (i.e., GLS decreased and GLS2 increased). CLAV normalized the METH-induced GLS deficit but not the increase in GLS2. In summary, CLAV reduced acute and sensitized locomotor responses to METH and normalized the METH-induced reduction of GLS gene expression in the NAC. Given that glutaminases belong to the ß-lactamase superfamily and CLAV is a ß-lactamase inhibitor, our data point toward studying glutaminase as a therapeutic target of CLAV.
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Estimulantes del Sistema Nervioso Central , Ácido Clavulánico , Glutaminasa , Metanfetamina , Núcleo Accumbens , ARN Mensajero , Animales , Metanfetamina/farmacología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Glutaminasa/metabolismo , Masculino , Ácido Clavulánico/farmacología , ARN Mensajero/metabolismo , ARN Mensajero/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Ratones Endogámicos C57BL , Ratones , Locomoción/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Relación Dosis-Respuesta a DrogaRESUMEN
It was previously shown in striatal slices obtained from male rats that insulin excites cholinergic interneurons and increases dopamine (DA) release via α4ß2 nicotinic receptors on DA terminals. The effect of insulin on DA release was blocked either by maintaining rats on a high sugar-high fat (HS-HF) diet that induced hyperinsulinemia and nucleus accumbens (NAc) insulin receptor insensitivity, or applying the α4ß2 antagonist DHßE. In vivo, NAc shell insulin inactivation decreased a glucose lick microstructure parameter indicative of hedonic impact in male and female rats, and prevented flavor-nutrient learning, tested only in males. The HS-HF diet decreased hedonic impact in males but not females, and prevented flavor-nutrient learning, tested only in males. The present study extends testing to more fully assess the translation of brain slice results to the behaving rat. Insulin inactivation by antibody microinjection in NAc shell was found to decrease the number of lick bursts emitted and average lick burst size, measures of incentive motivation and hedonic impact respectively, for a wide range of glucose concentrations in male and female rats. In contrast, the HS-HF diet decreased these lick parameters in males but not females. Follow-up two-bottle choice tests for 10 % versus 40 % glucose showed decreased intake of both concentrations by males but increased intake of 40 % glucose by females. In a further set of experiments, it was predicted that α4ß2 receptor blockade would induce the same behavioral effects as insulin inactivation. In females, DHßE microinjection in NAc shell decreased both lick parameters for glucose as predicted, but in males only the number of lick bursts emitted was decreased. DHßE also decreased the number of lick bursts emitted for saccharin by females but not males. Finally, DHßE microinjection in NAc shell decreased flavor-nutrient learning in both sexes. The few discrepancies seen with regard to the hypothesized insulin-nicotinic-dopaminergic regulation of behavioral responses to nutritive sweetener, and its inhibition by HS-HF diet, are discussed with reference to sex differences in DA dynamics, female resistance to diet-induced metabolic morbidities, and extra-striatal cholinergic inputs to NAc.
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Dieta Alta en Grasa , Dopamina , Insulina , Núcleo Accumbens , Animales , Masculino , Femenino , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Insulina/metabolismo , Dopamina/metabolismo , Ratas , Dieta Alta en Grasa/efectos adversos , Caracteres Sexuales , Azúcares de la Dieta , Ratas Sprague-Dawley , Glucosa/metabolismoRESUMEN
Exposure to alcohol during adolescence impacts cortical and limbic brain regions undergoing maturation. In rodent models, long-term effects on behavior and neurophysiology have been described after adolescent intermittent ethanol (AIE), especially in males. We hypothesized that AIE in female rats increases conditional approach to a reward-predictive cue and corresponding neuronal activity in the orbitofrontal cortex (OFC) and nucleus accumbens (NAc). We evaluated behavior and neuronal firing after AIE (5 g/kg intragastric) or water (CON) in adult female rats. Both AIE and CON groups expressed a ST phenotype, and AIE marginally increased sign-tracking (ST) and decreased goal-tracking (GT) metrics. NAc neurons exhibited phasic firing patterns to the conditional stimulus (CS), with no differences between groups. In contrast, neuronal firing in the OFC of AIE animals was greater at CS onset and offset than in CON animals. During reward omission, OFC responses to CS offset normalized to CON levels, but enhanced OFC firing to CS onset persisted in AIE. We suggest that the enhanced OFC neural activity observed in AIE rats to the CS could contribute to behavioral inflexibility. Ultimately, AIE persistently impacts the neurocircuitry of reward-motivated behavior in female rats.
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Etanol , Núcleo Accumbens , Corteza Prefrontal , Recompensa , Animales , Femenino , Corteza Prefrontal/fisiología , Corteza Prefrontal/efectos de los fármacos , Ratas , Etanol/farmacología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiología , Neuronas/fisiología , Neuronas/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Señales (Psicología) , Ratas Sprague-DawleyRESUMEN
A total of 3102 neurons were recorded before and following acute and chronic methylphenidate (MPD) administration. Acute MPD exposure elicits mainly increases in neuronal and behavioral activity in dose-response characteristics. The response to chronic MPD exposure, as compared to acute 0.6, 2.5, or 10.0 mg/kg MPD administration, elicits electrophysiological and behavioral sensitization in some animals and electrophysiological and behavioral tolerance in others when the neuronal recording evaluations were performed based on the animals' behavioral responses, or amount of locomotor activity, to chronic MPD exposure. The majority of neurons recorded from those expressing behavioral sensitization responded to chronic MPD with further increases in firing rate as compared to the initial MPD responses. The majority of neurons recorded from animals expressing behavioral tolerance responded to chronic MPD with decreases in their firing rate as compared to the initial MPD exposures. Each of the six brain areas studied-the ventral tegmental area, locus coeruleus, dorsal raphe, nucleus accumbens, prefrontal cortex, and caudate nucleus (VTA, LC, DR, NAc, PFC, and CN)-responds significantly (p < 0.001) differently to MPD, suggesting that each one of the above brain areas exhibits different roles in the response to MPD. Moreover, this study demonstrates that it is essential to evaluate neuronal activity responses to psychostimulants based on the animals' behavioral responses to acute and chronic effects of the drug from several brain areas simultaneously to obtain accurate information on each area's role in response to the drug.
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Conducta Animal , Núcleo Caudado , Metilfenidato , Neuronas , Núcleo Accumbens , Corteza Prefrontal , Área Tegmental Ventral , Animales , Metilfenidato/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiología , Ratas , Neuronas/efectos de los fármacos , Neuronas/fisiología , Neuronas/metabolismo , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/fisiología , Núcleo Caudado/metabolismo , Masculino , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/fisiología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiología , Conducta Animal/efectos de los fármacos , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/fisiología , Ratas Sprague-Dawley , Núcleo Dorsal del Rafe/efectos de los fármacos , Núcleo Dorsal del Rafe/fisiología , Núcleo Dorsal del Rafe/metabolismo , Estimulantes del Sistema Nervioso Central/farmacologíaRESUMEN
It has been recently established that GPR158, a class C orphan G protein-coupled receptor, serves as a metabotropic glycine receptor. GPR158 is highly expressed in the nucleus accumbens (NAc), a major input structure of the basal ganglia that integrates information from cortical and subcortical structures to mediate goal-directed behaviors. However, whether glycine modulates neuronal activity in the NAc through GPR158 activation has not been investigated yet. Using whole-cell patch-clamp recordings, we found that glycine-dependent activation of GPR158 increased the firing rate of NAc medium spiny neurons (MSNs) while it failed to significantly affect the excitability of cholinergic interneurons (CIN). In MSNs GPR158 activation reduced the latency to fire, increased the action potential half-width, and reduced action potential afterhyperpolarization, effects that are all consistent with negative modulation of potassium M-currents, that in the central nervous system are mainly carried out by Kv7/KCNQ-channels. Indeed, we found that the GPR158-induced increase in MSN excitability was associated with decreased M-current amplitude, and selective pharmacological inhibition of the M-current mimicked and occluded the effects of GPR158 activation. In addition, when the protein kinase A (PKA) or extracellular signal-regulated kinase (ERK) signaling was pharmacologically blocked, modulation of MSN excitability by GPR158 activation was suppressed. Moreover, GPR158 activation increased the phosphorylation of ERK and Kv7.2 serine residues. Collectively, our findings suggest that GPR158/PKA/ERK signaling controls MSN excitability via Kv7.2 modulation. Glycine-dependent activation of GPR158 may significantly affect MSN firing in vivo, thus potentially mediating specific aspects of goal-induced behaviors.