RESUMO
Chronic pain can induce mood disorders and cognitive dysfunctions, such as anxiety, depression, and learning and memory impairment in humans. However, the specific neural network involved in anxiety- and depression-like behaviors and learning and memory impairment caused by chronic pain remains poorly understood. In this study, behavioral test results showed that chronic pain induced anxiety- and depression-like behaviors, and learning and memory impairment in male mice. c-Fos immunofluorescence and fiber photometry recording showed that glutamatergic neurons in the LH of mice with chronic pain were selectively activated. Next, the glutamatergic neurons of LH in normal mice were activated using optogenetic and chemogenetic methods, which recapitulates some of the depressive-like behaviors, as well as memory impairment, but not anxiety-like behavior. Finally, inhibition of glutamatergic neurons in the LH of mice with chronic pain, effectively relieved anxiety- and depression-like behaviors and learning and memory impairment. Taken together, our findings suggest that hyperexcitation of glutamatergic neurons in the LH is involved in depression-like behavior and learning and memory impairment induced by chronic pain.
RESUMO
Clinical studies have shown that the mediodorsal thalamus (MD) may play an important role in the development of depression. However, the molecular and circuit mechanisms by which the mediodorsal thalamus (MD) participates in the pathological processes of depression remain unclear. Here, we show that in male chronic social defeat stress (CSDS) mice, the calcium signaling activity of glutamatergic neurons in MD is reduced. By combining conventional neurotracer and transneuronal virus tracing techniques, we identify a synaptic circuit connecting MD and medial prefrontal cortex (mPFC) in the mouse. Brain slice electrophysiology and fiber optic recordings reveal that the reduced activity of MD glutamatergic neurons leads to an excitatory-inhibitory imbalance of pyramidal neurons in mPFC. Furthermore, activation of MD glutamatergic neurons restores the electrophysiological properties abnormal in mPFC. Optogenetic activation of the MD-mPFC circuit ameliorates anxiety and depression-like behaviors in CSDS mice. Taken together, these data support the critical role of MD-mPFC circuit on CSDS-induced depression-like behavior and provide a potential mechanistic explanation for depression.
Assuntos
Depressão , Camundongos Endogâmicos C57BL , Vias Neurais , Optogenética , Córtex Pré-Frontal , Derrota Social , Estresse Psicológico , Animais , Córtex Pré-Frontal/metabolismo , Estresse Psicológico/fisiopatologia , Masculino , Depressão/fisiopatologia , Vias Neurais/fisiopatologia , Camundongos , Núcleo Mediodorsal do Tálamo , Neurônios/fisiologia , Neurônios/metabolismo , Células Piramidais/fisiologiaRESUMO
Clinical studies have shown that social defeat is an important cause of mood-related disorders, accompanied by learning and memory impairment in humans. The mechanism of mood-related disorders has been widely studied. However, the specific neural network involved in learning and memory impairment caused by social defeat remains unclear. In this study, behavioral test results showed that the mice induced both learning and memory impairments and mood-related disorders after exposure to chronic social defeat stress (CSDS). c-Fos immunofluorescence and fiber photometry recording confirmed that CaMKIIα expressing neurons of the piriform cortex (PC) were selectively activated by exposure to CSDS. Next, chemogenetics and optogenetics were performed to activate PC CaMKIIα expressing neurons, which showed learning and memory impairment but not mood-related disorders. Furthermore, chemogenetic inhibition of PC CaMKIIα expressing neurons significantly alleviated learning and memory impairment induced by exposure to CSDS but did not relieve mood-related disorders. Therefore, our data suggest that the overactivation of PC CaMKIIα expressing neurons mediates CSDS-induced learning and memory impairment, but not mood-related disorders, and provides a potential therapeutic target for learning and memory impairment induced by social defeat.
Assuntos
Córtex Piriforme , Derrota Social , Animais , Ansiedade , Humanos , Transtornos da Memória , Camundongos , Estresse PsicológicoRESUMO
Hyperthyroidism has been identified as a risk factor for cognitive disorders. The hippocampus is a key brain region associated with cognitive function, among which excitatory synapse transmission plays an important role in the process of learning and memory. However, the mechanism by which hyperthyroidism leads to cognitive dysfunction through a synaptic mechanism remains unknown. We investigated the synaptic mechanisms in the effects of hyperthyroidism in an animal model that involved repeated injection of triiodothyronine (T3). These mice displayed impaired learning and memory in the Novel object recognition test, Y-maze test, and Morris Water Maze test, as well as elevated anxiety in the elevated plus maze. Mature dendritic spines in the hippocampal CA1 region of hyperthyroid mice were significantly decreased, accompanied by decreased level of AMPA- and NMDA-type glutamate receptors in the hippocampus. In primary cultured hippocampal neurons, levels of AMPA- and NMDA-type glutamate receptors also decreased and whole-cell patch-clamp recording revealed that excitatory synaptic function was obviously attenuated after T3 treatment. Notably, pharmacological activation of AMPAR or NMDAR by intraperitoneal injection of CX546, an AMPAR agonist, or NMDA, an NMDAR agonist can restore excitatory synaptic function and corrected impaired learning and memory deficit in hyperthyroid mice. Together, our findings uncovered a previously unrecognized AMPAR and NMDAR-dependent mechanism involved in regulating hippocampal excitatory synaptic transmission and learning and memory disorders in hyperthyroidism.