RESUMO
Recent insights into the neural circuits controlling energy balance and glucose homeostasis have rekindled the hope for development of novel treatments for obesity and diabetes. However, many therapies contribute relatively modest beneficial gains with accompanying side effects, and the mechanisms of action for other interventions remain undefined. This Review summarizes current knowledge linking the neural circuits regulating energy and glucose balance with current and potential pharmacotherapeutic and surgical interventions for the treatment of obesity and diabetes.
Assuntos
Metabolismo Energético , Vias Neurais , Animais , Depressores do Apetite/uso terapêutico , Encéfalo/fisiopatologia , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/metabolismo , Metabolismo Energético/efeitos dos fármacos , Humanos , Vias Neurais/efeitos dos fármacos , Obesidade/tratamento farmacológico , Obesidade/metabolismoRESUMO
All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance-use disorders1,2. Another recently appreciated mechanism of neural circuit plasticity is mediated through activity-regulated changes in myelin that can tune circuit function and influence cognitive behaviour3-7. Here we explore the role of myelin plasticity in dopaminergic circuitry and reward learning. We demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by optogenetic stimulation of dopaminergic neurons, optogenetic inhibition of GABAergic neurons, or administration of morphine. These oligodendroglial changes are evident selectively within the ventral tegmental area but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens. Genetic blockade of oligodendrogenesis dampens dopamine release dynamics in nucleus accumbens and impairs behavioural conditioning to morphine. Taken together, these findings underscore a critical role for oligodendrogenesis in reward learning and identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward.
Assuntos
Analgésicos Opioides , Bainha de Mielina , Vias Neurais , Plasticidade Neuronal , Recompensa , Área Tegmentar Ventral , Animais , Feminino , Masculino , Camundongos , Analgésicos Opioides/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Morfina/farmacologia , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Núcleo Accumbens/citologia , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/citologia , Oligodendroglia/efeitos dos fármacos , Optogenética , Área Tegmentar Ventral/fisiologia , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Linhagem da CélulaRESUMO
The most successful obesity therapeutics, glucagon-like peptide-1 receptor (GLP1R) agonists, cause aversive responses such as nausea and vomiting1,2, effects that may contribute to their efficacy. Here, we investigated the brain circuits that link satiety to aversion, and unexpectedly discovered that the neural circuits mediating these effects are functionally separable. Systematic investigation across drug-accessible GLP1R populations revealed that only hindbrain neurons are required for the efficacy of GLP1-based obesity drugs. In vivo two-photon imaging of hindbrain GLP1R neurons demonstrated that most neurons are tuned to either nutritive or aversive stimuli, but not both. Furthermore, simultaneous imaging of hindbrain subregions indicated that area postrema (AP) GLP1R neurons are broadly responsive, whereas nucleus of the solitary tract (NTS) GLP1R neurons are biased towards nutritive stimuli. Strikingly, separate manipulation of these populations demonstrated that activation of NTSGLP1R neurons triggers satiety in the absence of aversion, whereas activation of APGLP1R neurons triggers strong aversion with food intake reduction. Anatomical and behavioural analyses revealed that NTSGLP1R and APGLP1R neurons send projections to different downstream brain regions to drive satiety and aversion, respectively. Importantly, GLP1R agonists reduce food intake even when the aversion pathway is inhibited. Overall, these findings highlight NTSGLP1R neurons as a population that could be selectively targeted to promote weight loss while avoiding the adverse side effects that limit treatment adherence.
Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1 , Neurônios , Rombencéfalo , Resposta de Saciedade , Núcleo Solitário , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Animais , Rombencéfalo/fisiologia , Rombencéfalo/metabolismo , Rombencéfalo/efeitos dos fármacos , Camundongos , Masculino , Núcleo Solitário/metabolismo , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Neurônios/efeitos dos fármacos , Resposta de Saciedade/efeitos dos fármacos , Resposta de Saciedade/fisiologia , Área Postrema/metabolismo , Área Postrema/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Saciação/fisiologia , Saciação/efeitos dos fármacos , Feminino , Camundongos Endogâmicos C57BL , Fármacos Antiobesidade/farmacologia , Obesidade/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Vias Neurais/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologiaRESUMO
The suprachiasmatic nucleus (SCN) serves as the body's master circadian clock that adaptively coordinates changes in physiology and behaviour in anticipation of changing requirements throughout the 24-h day-night cycle1-4. For example, the SCN opposes overnight adipsia by driving water intake before sleep5,6, and by driving the secretion of anti-diuretic hormone7,8 and lowering body temperature9,10 to reduce water loss during sleep11. These responses can also be driven by central osmo-sodium sensors to oppose an unscheduled rise in osmolality during the active phase12-16. However, it is unknown whether osmo-sodium sensors require clock-output networks to drive homeostatic responses. Here we show that a systemic salt injection (hypertonic saline) given at Zeitgeber time 19-a time at which SCNVP (vasopressin) neurons are inactive-excited SCNVP neurons and decreased non-shivering thermogenesis (NST) and body temperature. The effects of hypertonic saline on NST and body temperature were prevented by chemogenetic inhibition of SCNVP neurons and mimicked by optogenetic stimulation of SCNVP neurons in vivo. Combined anatomical and electrophysiological experiments revealed that osmo-sodium-sensing organum vasculosum lamina terminalis (OVLT) neurons expressing glutamic acid decarboxylase (OVLTGAD) relay this information to SCNVP neurons via an excitatory effect of γ-aminobutyric acid (GABA). Optogenetic activation of OVLTGAD neuron axon terminals excited SCNVP neurons in vitro and mimicked the effects of hypertonic saline on NST and body temperature in vivo. Furthermore, chemogenetic inhibition of OVLTGAD neurons blunted the effects of systemic hypertonic saline on NST and body temperature. Finally, we show that hypertonic saline significantly phase-advanced the circadian locomotor activity onset of mice. This effect was mimicked by optogenetic activation of the OVLTGADâ SCNVP pathway and was prevented by chemogenetic inhibition of OVLTGAD neurons. Collectively, our findings provide demonstration that clock time can be regulated by non-photic physiologically relevant cues, and that such cues can drive unscheduled homeostatic responses via clock-output networks.
Assuntos
Relógios Circadianos/fisiologia , Vias Neurais , Neurônios/metabolismo , Sódio/metabolismo , Núcleo Supraquiasmático/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Relógios Circadianos/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Ingestão de Líquidos/efeitos dos fármacos , Glutamato Descarboxilase/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Vias Neurais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Optogenética , Organum Vasculosum/citologia , Organum Vasculosum/efeitos dos fármacos , Organum Vasculosum/enzimologia , Organum Vasculosum/fisiologia , Concentração Osmolar , Solução Salina Hipertônica/administração & dosagem , Solução Salina Hipertônica/metabolismo , Solução Salina Hipertônica/farmacologia , Sódio/administração & dosagem , Sódio/farmacologia , Núcleo Supraquiasmático/citologia , Núcleo Supraquiasmático/efeitos dos fármacos , Vasopressinas/metabolismoAssuntos
Apetite , Obesidade , Humanos , Animais , Apetite/efeitos dos fármacos , Obesidade/tratamento farmacológico , Camundongos , Fármacos Antiobesidade/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Modafinila/farmacologia , Modafinila/uso terapêutico , Vias Neurais/efeitos dos fármacosRESUMO
Sodium is the main cation in the extracellular fluid and it regulates various physiological functions. Depletion of sodium in the body increases the hedonic value of sodium taste, which drives animals towards sodium consumption1,2. By contrast, oral sodium detection rapidly quenches sodium appetite3,4, suggesting that taste signals have a central role in sodium appetite and its satiation. Nevertheless, the neural mechanisms of chemosensory-based appetite regulation remain poorly understood. Here we identify genetically defined neural circuits in mice that control sodium intake by integrating chemosensory and internal depletion signals. We show that a subset of excitatory neurons in the pre-locus coeruleus express prodynorphin, and that these neurons are a critical neural substrate for sodium-intake behaviour. Acute stimulation of this population triggered robust ingestion of sodium even from rock salt, while evoking aversive signals. Inhibition of the same neurons reduced sodium consumption selectively. We further demonstrate that the oral detection of sodium rapidly suppresses these sodium-appetite neurons. Simultaneous in vivo optical recording and gastric infusion revealed that sodium taste-but not sodium ingestion per se-is required for the acute modulation of neurons in the pre-locus coeruleus that express prodynorphin, and for satiation of sodium appetite. Moreover, retrograde-virus tracing showed that sensory modulation is in part mediated by specific GABA (γ-aminobutyric acid)-producing neurons in the bed nucleus of the stria terminalis. This inhibitory neural population is activated by sodium ingestion, and sends rapid inhibitory signals to sodium-appetite neurons. Together, this study reveals a neural architecture that integrates chemosensory signals and the internal need to maintain sodium balance.
Assuntos
Regulação do Apetite/efeitos dos fármacos , Regulação do Apetite/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Sódio/farmacologia , Paladar/efeitos dos fármacos , Paladar/fisiologia , Administração Oral , Animais , Regulação do Apetite/genética , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Ingestão de Alimentos/genética , Ingestão de Alimentos/fisiologia , Encefalinas/metabolismo , Feminino , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Homeostase/efeitos dos fármacos , Homeostase/genética , Homeostase/fisiologia , Locus Cerúleo/citologia , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/fisiologia , Masculino , Camundongos , Motivação/efeitos dos fármacos , Vias Neurais/citologia , Vias Neurais/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Precursores de Proteínas/metabolismo , Resposta de Saciedade/efeitos dos fármacos , Resposta de Saciedade/fisiologia , Sódio/administração & dosagem , Paladar/genéticaRESUMO
Closed head injury is a prevalent form of traumatic brain injury with poorly understood effects on cortical neural circuits. Given the emotional and behavioral impairments linked to closed head injury, it is vital to uncover brain functional deficits and their driving mechanisms. In this study, we employed a robust viral tracing technique to identify the alteration of the neural pathway connecting the medial prefrontal cortex to the basolateral amygdala, and we observed the disruptions in neuronal projections between the medial prefrontal cortex and the basolateral amygdala following closed head injury. Remarkably, our results highlight that ZL006, an inhibitor targeting PSD-95/nNOS interaction, stands out for its ability to selectively reverse these aberrations. Specifically, ZL006 effectively mitigates the disruptions in neuronal projections from the medial prefrontal cortex to basolateral amygdala induced by closed head injury. Furthermore, using chemogenetic approaches, we elucidate that activating the medial prefrontal cortex projections to the basolateral amygdala circuit produces anxiolytic effects, aligning with the therapeutic potential of ZL006. Additionally, ZL006 administration effectively mitigates astrocyte activation, leading to the restoration of medial prefrontal cortex glutamatergic neuron activity. Moreover, in the context of attenuating anxiety-like behaviors through ZL006 treatment, we observe a reduction in closed head injury-induced astrocyte engulfment, which may correlate with the observed decrease in dendritic spine density of medial prefrontal cortex glutamatergic neurons.
Assuntos
Tonsila do Cerebelo , Ansiedade , Traumatismos Cranianos Fechados , Córtex Pré-Frontal , Animais , Córtex Pré-Frontal/efeitos dos fármacos , Masculino , Traumatismos Cranianos Fechados/complicações , Ansiedade/tratamento farmacológico , Tonsila do Cerebelo/efeitos dos fármacos , Camundongos , Vias Neurais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Proteína 4 Homóloga a Disks-Large/metabolismoRESUMO
Resting tremor is the most common presenting motor symptom in Parkinson's disease (PD). The supplementary motor area (SMA) is a main target of the basal-ganglia-thalamo-cortical circuit and has direct, facilitatory connections with the primary motor cortex (M1), which is important for the execution of voluntary movement. Dopamine potentially modulates SMA and M1 activity, and both regions have been implicated in resting tremor. This study investigated SMA-M1 connectivity in individuals with PD ON and OFF dopamine medication, and whether SMA-M1 connectivity is implicated in resting tremor. Dual-site transcranial magnetic stimulation was used to measure SMA-M1 connectivity in PD participants ON and OFF levodopa. Resting tremor was measured using electromyography and accelerometry. Stimulating SMA inhibited M1 excitability OFF levodopa, and facilitated M1 excitability ON levodopa. ON medication, SMA-M1 facilitation was significantly associated with smaller tremor than SMA-M1 inhibition. The current findings contribute to our understanding of the neural networks involved in PD which are altered by levodopa medication and provide a neurophysiological basis for the development of interventions to treat resting tremor.
Assuntos
Antiparkinsonianos , Eletromiografia , Levodopa , Córtex Motor , Doença de Parkinson , Estimulação Magnética Transcraniana , Tremor , Humanos , Levodopa/uso terapêutico , Levodopa/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Masculino , Córtex Motor/efeitos dos fármacos , Córtex Motor/fisiopatologia , Feminino , Tremor/fisiopatologia , Tremor/tratamento farmacológico , Idoso , Pessoa de Meia-Idade , Estimulação Magnética Transcraniana/métodos , Antiparkinsonianos/uso terapêutico , Antiparkinsonianos/farmacologia , Vias Neurais/fisiopatologia , Vias Neurais/efeitos dos fármacos , Potencial Evocado Motor/efeitos dos fármacos , Potencial Evocado Motor/fisiologiaRESUMO
In a changing environment, animals must process spatial signals in a flexible manner. The rat hippocampal formation projects directly upon the retrosplenial cortex, with most inputs arising from the dorsal subiculum and terminating in the granular retrosplenial cortex (area 29). The present study examined whether these same projections are required for spatial working memory and what happens when available spatial cues are altered. Consequently, injections of iDREADDs were made into the dorsal subiculum of rats. In a separate control group, GFP-expressing adeno-associated virus was injected into the dorsal subiculum. Both groups received intracerebral infusions within the retrosplenial cortex of clozapine, which in the iDREADDs rats should selectively disrupt the subiculum to retrosplenial projections. When tested on reinforced T-maze alternation, disruption of the subiculum to retrosplenial projections had no evident effect on the performance of those alternation trials when all spatial-cue types remained present and unchanged. However, the same iDREADDs manipulation impaired performance on all three alternation conditions when there was a conflict or selective removal of spatial cues. These findings reveal how the direct projections from the dorsal subiculum to the retrosplenial cortex support the flexible integration of different spatial cue types, helping the animal to adopt the spatial strategy that best meets current environmental demands.
Assuntos
Hipocampo , Ratos Long-Evans , Memória Espacial , Animais , Masculino , Ratos , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Sinais (Psicologia) , Clozapina/farmacologia , Clozapina/análogos & derivados , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Vias Neurais/fisiologia , Vias Neurais/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologiaRESUMO
Prenatal alcohol exposure is the foremost preventable etiology of intellectual disability and leads to a collection of diagnoses known as Fetal Alcohol Spectrum Disorders (FASD). Alcohol (EtOH) impacts diverse neural cell types and activity, but the precise functional pathophysiological effects on the human fetal cerebral cortex are unclear. Here, we used human cortical organoids to study the effects of EtOH on neurogenesis and validated our findings in primary human fetal neurons. EtOH exposure produced temporally dependent cellular effects on proliferation, cell cycle, and apoptosis. In addition, we identified EtOH-induced alterations in post-translational histone modifications and chromatin accessibility, leading to impairment of cAMP and calcium signaling, glutamatergic synaptic development, and astrocytic function. Proteomic spatial profiling of cortical organoids showed region-specific, EtOH-induced alterations linked to changes in cytoskeleton, gliogenesis, and impaired synaptogenesis. Finally, multi-electrode array electrophysiology recordings confirmed the deleterious impact of EtOH on neural network formation and activity in cortical organoids, which was validated in primary human fetal tissues. Our findings demonstrate progress in defining the human molecular and cellular phenotypic signatures of prenatal alcohol exposure on functional neurodevelopment, increasing our knowledge for potential therapeutic interventions targeting FASD symptoms.
Assuntos
Córtex Cerebral , Etanol , Vias Neurais , Neurogênese , Neurônios , Organoides , Feminino , Humanos , Masculino , Gravidez , Astrócitos/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/citologia , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Montagem e Desmontagem da Cromatina/genética , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/genética , Etanol/farmacologia , Transtornos do Espectro Alcoólico Fetal/etiologia , Transtornos do Espectro Alcoólico Fetal/genética , Feto/citologia , Perfilação da Expressão Gênica , Rede Nervosa/efeitos dos fármacos , Transtornos do Neurodesenvolvimento/induzido quimicamente , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Neurogênese/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Organoides/citologia , Organoides/efeitos dos fármacos , Organoides/patologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética , Proteômica , Sinapses/efeitos dos fármacos , Vias Neurais/efeitos dos fármacosRESUMO
Since the clinical introduction of general anesthesia, its underlying mechanisms have not been fully elucidated. The ventral tegmental area (VTA) and parabrachial nucleus (PBN) play pivotal roles in the mechanisms underlying general anesthesia. However, whether dopaminergic (DA) projections from the VTA to the PBN play a role in mediating the effects of general anesthesia is unclear. We microinjected 6-hydroxydopamine into the PBN to damage tyrosine hydroxylase positive (TH+) neurons and found a prolonged recovery time from propofol anesthesia. We used calcium fiber photometry recording to explore the activity of TH + neurons in the PBN. Then, we used chemogenetic and optogenetic approaches either activate the VTADA-PBN pathway, shortening the propofol anesthesia emergence time, or inhibit this pathway, prolonging the emergence time. These data indicate the crucial involvement of TH + neurons in the PBN in regulating emergence from propofol anesthesia, while the activation of the VTADA-PBN pathway facilitates the emergence of propofol anesthesia.
Assuntos
Anestésicos Intravenosos , Neurônios Dopaminérgicos , Núcleos Parabraquiais , Propofol , Ratos Sprague-Dawley , Área Tegmentar Ventral , Propofol/farmacologia , Animais , Área Tegmentar Ventral/efeitos dos fármacos , Masculino , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Núcleos Parabraquiais/efeitos dos fármacos , Núcleos Parabraquiais/fisiologia , Anestésicos Intravenosos/farmacologia , Ratos , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Período de Recuperação da Anestesia , Oxidopamina/farmacologiaRESUMO
BACKGROUND: The Default Mode Network (DMN) is a central neural network, with recent evidence indicating that it is composed of functionally distinct sub-networks. Methylphenidate (MPH) administration has been shown before to modulate impulsive behavior, though it is not yet clear whether these effects relate to MPH-induced changes in DMN connectivity. To address this gap, we assessed the impact of MPH administration on functional connectivity patterns within and between distinct DMN sub-networks and tested putative relations to variability in sub-scales of impulsivity. METHODS: Fifty-five right-handed healthy adults underwent two resting-state functional MRI (rs-fMRI) scans, following acute administration of either MPH (20 mg) or placebo, via a randomized double-blind placebo-controlled design. Graph modularity analysis was implemented to fractionate the DMN into distinct sub-networks based on the impact of MPH (vs. placebo) on DMN connectivity patterns with other neural networks. RESULTS: MPH administration led to an overall decreased DMN connectivity, particularly with the auditory, cinguloopercular, and somatomotor networks, and increased connectivity with the parietomedial network. Graph analysis revealed that the DMN could be fractionated into two distinct sub-networks, with one exhibiting MPH-induced increased connectivity and the other decreased connectivity. Decreased connectivity of the DMN sub-network with the cinguloopercular network following MPH administration was associated with elevated impulsivity and non-planning impulsiveness. CONCLUSION: Current findings highlight the intricate effects of MPH administration on DMN rs-fMRI connectivity, uncovering its opposing impact on distinct DMN sub-divisions. MPH-induced dynamics in DMN connectivity patterns with other neural networks may account for some of the effects of MPH administration on impulsive behavior.
Assuntos
Estimulantes do Sistema Nervoso Central , Rede de Modo Padrão , Imageamento por Ressonância Magnética , Metilfenidato , Rede Nervosa , Humanos , Metilfenidato/farmacologia , Metilfenidato/administração & dosagem , Adulto , Masculino , Imageamento por Ressonância Magnética/métodos , Feminino , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Rede de Modo Padrão/efeitos dos fármacos , Rede de Modo Padrão/diagnóstico por imagem , Adulto Jovem , Método Duplo-Cego , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiologia , Comportamento Impulsivo/efeitos dos fármacos , Conectoma/métodos , Encéfalo/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologiaRESUMO
Many retinal diseases lead to the loss of retinal neurons and cause visual impairment. The adult mammalian retina has little capacity for regeneration. By contrast, teleost fish functionally regenerate their retina following injury, and Müller glia (MG) are the source of regenerated neurons. The proneural transcription factor Ascl1 is upregulated in MG after retinal damage in zebrafish and is necessary for regeneration. Although Ascl1 is not expressed in mammalian MG after injury, forced expression of Ascl1 in mouse MG induces a neurogenic state in vitro and in vivo after NMDA (N-methyl-d-aspartate) damage in young mice. However, by postnatal day 16, mouse MG lose neurogenic capacity, despite Ascl1 overexpression. Loss of neurogenic capacity in mature MG is accompanied by reduced chromatin accessibility, suggesting that epigenetic factors limit regeneration. Here we show that MG-specific overexpression of Ascl1, together with a histone deacetylase inhibitor, enables adult mice to generate neurons from MG after retinal injury. The MG-derived neurons express markers of inner retinal neurons, synapse with host retinal neurons, and respond to light. Using an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), we show that the histone deacetylase inhibitor promotes accessibility at key gene loci in the MG, and allows more effective reprogramming. Our results thus provide a new approach for the treatment of blinding retinal diseases.
Assuntos
Regeneração Nervosa , Neurogênese , Neuroglia/citologia , Neurônios/citologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Epistasia Genética/efeitos dos fármacos , Feminino , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Masculino , Camundongos , Regeneração Nervosa/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Retina/citologia , Retina/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismoRESUMO
To thrive in dynamic environments, animals must be capable of rapidly and flexibly adapting behavioral responses to a changing context and internal state. Examples of behavioral flexibility include faster stimulus responses when attentive and slower responses when distracted. Contextual or state-dependent modulations may occur early in the cortical hierarchy and may be implemented via top-down projections from corticocortical or neuromodulatory pathways. However, the computational mechanisms mediating the effects of such projections are not known. Here, we introduce a theoretical framework to classify the effects of cell type-specific top-down perturbations on the information processing speed of cortical circuits. Our theory demonstrates that perturbation effects on stimulus processing can be predicted by intrinsic gain modulation, which controls the timescale of the circuit dynamics. Our theory leads to counterintuitive effects, such as improved performance with increased input variance. We tested the model predictions using large-scale electrophysiological recordings from the visual hierarchy in freely running mice, where we found that a decrease in single-cell intrinsic gain during locomotion led to an acceleration of visual processing. Our results establish a novel theory of cell type-specific perturbations, applicable to top-down modulation as well as optogenetic and pharmacological manipulations. Our theory links connectivity, dynamics, and information processing via gain modulation.SIGNIFICANCE STATEMENT To thrive in dynamic environments, animals adapt their behavior to changing circumstances and different internal states. Examples of behavioral flexibility include faster responses to sensory stimuli when attentive and slower responses when distracted. Previous work suggested that contextual modulations may be implemented via top-down inputs to sensory cortex coming from higher brain areas or neuromodulatory pathways. Here, we introduce a theory explaining how the speed at which sensory cortex processes incoming information is adjusted by changes in these top-down projections, which control the timescale of neural activity. We tested our model predictions in freely running mice, revealing that locomotion accelerates visual processing. Our theory is applicable to internal modulation as well as optogenetic and pharmacological manipulations and links circuit connectivity, dynamics, and information processing.
Assuntos
Córtex Cerebral/fisiologia , Tempo de Reação/fisiologia , Algoritmos , Animais , Atenção , Córtex Cerebral/efeitos dos fármacos , Simulação por Computador , Fenômenos Eletrofisiológicos , Camundongos , Modelos Psicológicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Neurônios/fisiologia , Optogenética , Tempo de Reação/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologiaRESUMO
Entorhinal cortex neurons make monosynaptic connections onto distal apical dendrites of CA1 and CA2 pyramidal neurons through the perforant path (PP) projection. Previous studies show that differences in dendritic properties and synaptic input density enable the PP inputs to produce a much stronger excitation of CA2 compared with CA1 pyramidal neurons. Here, using mice of both sexes, we report that the difference in PP efficacy varies substantially as a function of presynaptic firing rate. Although a single PP stimulus evokes a 5- to 6-fold greater EPSP in CA2 compared with CA1, a brief high-frequency train of PP stimuli evokes a strongly facilitating postsynaptic response in CA1, with relatively little change in CA2. Furthermore, we demonstrate that blockade of NMDARs significantly reduces strong temporal summation in CA1 but has little impact on that in CA2. As a result of the differences in the frequency- and NMDAR-dependent temporal summation, naturalistic patterns of presynaptic activity evoke CA1 and CA2 responses with distinct dynamics, differentially tuning CA1 and CA2 responses to bursts of presynaptic firing versus single presynaptic spikes, respectively.SIGNIFICANCE STATEMENT Recent studies have demonstrated that abundant entorhinal cortical innervation and efficient dendritic propagation enable hippocampal CA2 pyramidal neurons to produce robust excitation evoked by single cortical stimuli, compared with CA1. Here we uncovered, unexpectedly, that the difference in efficacy of cortical excitation varies substantially as a function of presynaptic firing rate. A burst of stimuli evokes a strongly facilitating response in CA1, but not in CA2. As a result, the postsynaptic response of CA1 and CA2 to presynaptic naturalistic firing displays contrasting temporal dynamics, which depends on the activation of NMDARs. Thus, whereas CA2 responds to single stimuli, CA1 is selectively recruited by bursts of cortical input.
Assuntos
Região CA1 Hipocampal/fisiologia , Região CA2 Hipocampal/fisiologia , Córtex Cerebral/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Células Piramidais/fisiologia , Sinapses/fisiologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Região CA2 Hipocampal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , Antagonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-B/farmacologia , Masculino , Camundongos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Técnicas de Patch-Clamp , Células Piramidais/efeitos dos fármacos , Sinapses/efeitos dos fármacosRESUMO
Blood pressure is controlled by endocrine, autonomic, and behavioral responses that maintain blood volume and perfusion pressure at levels optimal for survival. Although it is clear that central angiotensin type 1a receptors (AT1aR; encoded by the Agtr1a gene) influence these processes, the neuronal circuits mediating these effects are incompletely understood. The present studies characterize the structure and function of AT1aR neurons in the lamina terminalis (containing the median preoptic nucleus and organum vasculosum of the lamina terminalis), thereby evaluating their roles in blood pressure control. Using male Agtr1a-Cre mice, neuroanatomical studies reveal that AT1aR neurons in the area are largely glutamatergic and send projections to the paraventricular nucleus of the hypothalamus (PVN) that appear to synapse onto vasopressin-synthesizing neurons. To evaluate the functionality of these lamina terminalis AT1aR neurons, we virally delivered light-sensitive opsins and then optogenetically excited or inhibited the neurons while evaluating cardiovascular parameters or fluid intake. Optogenetic excitation robustly elevated blood pressure, water intake, and sodium intake, while optogenetic inhibition produced the opposite effects. Intriguingly, optogenetic excitation of these AT1aR neurons of the lamina terminalis also resulted in Fos induction in vasopressin neurons within the PVN and supraoptic nucleus. Further, within the PVN, selective optogenetic stimulation of afferents that arise from these lamina terminalis AT1aR neurons induced glutamate release onto magnocellular neurons and was sufficient to increase blood pressure. These cardiovascular effects were attenuated by systemic pretreatment with a vasopressin-1a-receptor antagonist. Collectively, these data indicate that excitation of lamina terminalis AT1aR neurons induces neuroendocrine and behavioral responses that increase blood pressure.SIGNIFICANCE STATEMENT Hypertension is a widespread health problem and risk factor for cardiovascular disease. Although treatments exist, a substantial percentage of patients suffer from "drug-resistant" hypertension, a condition associated with increased activation of brain angiotensin receptors, enhanced sympathetic nervous system activity, and elevated vasopressin levels. The present study highlights a role for angiotensin Type 1a receptor expressing neurons located within the lamina terminalis in regulating endocrine and behavioral responses that are involved in maintaining cardiovascular homeostasis. More specifically, data presented here reveal functional excitatory connections between angiotensin-sensitive neurons in the lamina terminals and vasopressin neurons in the paraventricular nucleus of the hypothalamus, and further indicate that activation of this circuit raises blood pressure. These neurons may be a promising target for antihypertensive therapeutics.
Assuntos
Angiotensinas/farmacologia , Arginina Vasopressina/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Vasoconstritores/farmacologia , Animais , Núcleo Basal de Meynert/efeitos dos fármacos , Núcleo Basal de Meynert/metabolismo , Ingestão de Líquidos/efeitos dos fármacos , Genes fos/efeitos dos fármacos , Ácido Glutâmico/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Optogenética , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptores de Vasopressinas/efeitos dos fármacos , Sódio na DietaRESUMO
Behaviours such as eating, copulating, defending oneself or taking addictive drugs begin with a motivation to initiate the behaviour. Both this motivational drive and the behaviours that follow are influenced by past and present experience with the reinforcing stimuli (such as drugs or energy-rich foods) that increase the likelihood and/or strength of the behavioural response (such as drug taking or overeating). At a cellular and circuit level, motivational drive is dependent on the concentration of extrasynaptic dopamine present in specific brain areas such as the striatum. Cues that predict a reinforcing stimulus also modulate extrasynaptic dopamine concentrations, energizing motivation. Repeated administration of the reinforcer (drugs, energy-rich foods) generates conditioned associations between the reinforcer and the predicting cues, which is accompanied by downregulated dopaminergic response to other incentives and downregulated capacity for top-down self-regulation, facilitating the emergence of impulsive and compulsive responses to food or drug cues. Thus, dopamine contributes to addiction and obesity through its differentiated roles in reinforcement, motivation and self-regulation, referred to here as the 'dopamine motive system', which, if compromised, can result in increased, habitual and inflexible responding. Thus, interventions to rebalance the dopamine motive system might have therapeutic potential for obesity and addiction.
Assuntos
Comportamento Aditivo/tratamento farmacológico , Dopamina/farmacologia , Dependência de Alimentos/tratamento farmacológico , Motivação/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Animais , Comportamento Aditivo/fisiopatologia , Dopamina/metabolismo , Humanos , Reforço PsicológicoRESUMO
BACKGROUND: Nitric oxide and GnRH are biological factors that participate in the regulation of reproductive functions. To our knowledge, there are no studies that link NO and GnRH in the sympathetic ganglia. Thus, the aim of the present work was to investigate the influence of NO on GnRH release from the coeliac ganglion and its effect on luteal regression at the end of pregnancy in the rat. METHODS: The ex vivo system composed by the coeliac ganglion, the superior ovarian nerve, and the ovary of rats on day 21 of pregnancy was incubated for 180 min with the addition, into the ganglionic compartment, of L-NG-nitro arginine methyl ester (L-NAME), a non-selective NO synthase inhibitor. The control group consisted in untreated organ systems. RESULTS: The addition of L-NAME in the coeliac ganglion compartment decreased NO as well as GnRH release from the coeliac ganglion. In the ovarian compartment, and with respect to the control group, we observed a reduced release of GnRH, NO, and noradrenaline, but an increased production of progesterone, estradiol, and expression of their limiting biosynthetic enzymes, 3ß-HSD and P450 aromatase, respectively. The inhibition of NO production by L-NAME in the coeliac ganglion compartment also reduced luteal apoptosis, lipid peroxidation, and nitrotyrosine, whereas it increased the total antioxidant capacity within the corpora lutea. CONCLUSION: Collectively, the results indicate that NO production by the coeliac ganglion modulates the physiology of the ovary and luteal regression during late pregnancy in rats.
Assuntos
Corpo Lúteo/inervação , Corpo Lúteo/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Óxido Nítrico/metabolismo , Animais , Interações Medicamentosas , Feminino , Gânglios Simpáticos/efeitos dos fármacos , Gânglios Simpáticos/metabolismo , Idade Gestacional , Hormônio Liberador de Gonadotropina/farmacologia , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/metabolismo , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Óxido Nítrico/farmacologia , Ovário/inervação , Ovário/metabolismo , Gravidez , RatosRESUMO
Alzheimer's disease is a progressive loss of memory and cognition, for which there is no cure. Although genetic studies initially suggested a primary role for amyloid-in Alzheimer's disease, treatment strategies targeted at reducing amyloid-have failed to reverse cognitive symptoms. These clinical findings suggest that cognitive decline is the result of a complex pathophysiology and that targeting amyloid-alone may not be sufficient to treat Alzheimer's disease. Instead, a broad outlook on neural-circuit-damaging processes may yield insights into new therapeutic strategies for curing memory loss in the disease.