RESUMO
Anorexia Nervosa (AN) is characterized by voluntary food restriction, excessive exercise and extreme body weight loss. AN is particularly prevalent among adolescent females experiencing stress-induced anxiety. We used the animal model, activity-based anorexia (ABA), which captures these characteristics of AN, to reveal the neurobiology underlying individual differences in AN vulnerability. Dorsal raphe (DR) regulates feeding and is recruited when coping inescapable stress. Through chemogenetic activation, we investigated the role of mPFC pyramidal neurons projecting to DR (mPFCâDR) in adolescent female mice's decision to eat or exercise following ABA induction. Although the DREADD ligand C21 could activate 44% of the mPFCâDR neurons, this did not generate significant group mean difference in the amount of food intake, compared to control ABA mice without chemogenetic activation. However, analysis of individuals' responses to C21 revealed a significant, positive correlation between food intake and mPFCâDR neurons that co-express cFos, a marker for neuronal activity. cFos expression by GABAergic interneurons (GABA-IN) in mPFC was significantly greater than that for the control ABA mice, indicating recruitment of GABA-IN by mPFCâDR neurons. Electron microscopic immunohistochemistry revealed that GABAergic innervation is 60% greater for the PFCâDR neurons than adjacent Layer 5 pyramidal neurons without projections to DR. Moreover, individual differences in this innervation correlated negatively with food intake specifically on the day of C21 administration. We propose that C21 activates two antagonistic pathways: (1) PFCâDR pyramidal neurons that promote food intake; and (2) GABA-IN in the mPFC that dampen food intake through feedback inhibition of mPFCâDR neurons.
Assuntos
Anorexia , Núcleo Dorsal da Rafe , Animais , Núcleo Dorsal da Rafe/metabolismo , Retroalimentação , Feminino , Neurônios GABAérgicos/metabolismo , Imidazóis , Interneurônios/metabolismo , Camundongos , Córtex Pré-Frontal/fisiologia , Células Piramidais/fisiologia , Sulfonamidas , Tiofenos , Ácido gama-Aminobutírico/metabolismoRESUMO
Food restriction (FR) evokes running, which may promote adaptive foraging in times of food scarcity, but can become lethal if energy expenditure exceeds caloric availability. Here, we demonstrate that chemogenetic activation of either the general medial prefrontal cortex (mPFC) pyramidal cell population, or the subpopulation projecting to dorsal striatum (DS) drives running specifically during hours preceding limited food availability, and not during ad libitum food availability. Conversely, suppression of mPFC pyramidal cells generally, or targeting mPFC-to-DS cells, reduced wheel running specifically during FR and not during ad libitum food access. Post mortem c-Fos analysis and electron microscopy of mPFC layer 5 revealed distinguishing characteristics of mPFC-to-DS cells, when compared to neighboring non-DS-projecting pyramidal cells: 1) greater recruitment of GABAergic activity and 2) less axo-somatic GABAergic innervation. Together, these attributes position the mPFC-to-DS subset of pyramidal cells to dominate mPFC excitatory outflow, particularly during FR, revealing a specific and causal role for mPFC-to-DS control of the decision to run during food scarcity. Individual differences in GABAergic activity correlate with running response to further support this interpretation. FR enhancement of PFC-to-DS activity may influence neural circuits both in studies using FR to motivate animal behavior and in human conditions hallmarked by FR.
Assuntos
Restrição Calórica/tendências , Tomada de Decisões/fisiologia , Metabolismo Energético/fisiologia , Rede Nervosa/metabolismo , Córtex Pré-Frontal/metabolismo , Corrida/fisiologia , Animais , Tomada de Decisões/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora , Rede Nervosa/química , Rede Nervosa/efeitos dos fármacos , Piperazinas/administração & dosagem , Piperazinas/metabolismo , Córtex Pré-Frontal/química , Córtex Pré-Frontal/efeitos dos fármacos , Células Piramidais/química , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Corrida/psicologiaRESUMO
Expression of the glutamate transporter GLT-1 in neurons has been shown to be important for synaptic mitochondrial function in the cerebral cortex. Here we determined whether neuronal GLT-1 plays a similar role in the hippocampus and striatum, using conditional GLT-1 knockout mice in which GLT-1 was inactivated in neurons by expression of synapsin-Cre (synGLT-1 KO). Ex vivo 13C-labelling using [1,2-13C]acetate, representing astrocytic metabolism, yielded increased [4,5-13C]glutamate levels, suggesting increased astrocyte-neuron glutamine transfer, in the striatum but not in the hippocampus of the synGLT-1 KO. Moreover, aspartate concentrations were reduced - 38% compared to controls in the hippocampus and the striatum of the synGLT-1 KO. Mitochondria isolated from the hippocampus of synGLT-1 KO mice exhibited a lower oxygen consumption rate in the presence of oligomycin A, indicative of a decreased proton leak across the mitochondrial membrane, whereas the ATP production rate was unchanged. Electron microscopy revealed reduced mitochondrial inter-cristae distance within excitatory synaptic terminals in the hippocampus and striatum of the synGLT-1 KO. Finally, dilution of 13C-labelling originating from [U-13C]glucose, caused by metabolism of unlabelled glutamate, was reduced in hippocampal synGLT-1 KO synaptosomes, suggesting that neuronal GLT-1 provides glutamate for synaptic tricarboxylic acid cycle metabolism. Collectively, these data demonstrate an important role of neuronal expression of GLT-1 in synaptic mitochondrial metabolism in the forebrain.