RESUMEN
Memory systems ought to store and discriminate representations of similar experiences in order to efficiently guide future decisions. This problem is solved by pattern separation, implemented in the dentate gyrus (DG) by granule cells to support episodic memory formation. Pattern separation is enabled by tonic inhibitory bombardment generated by multiple GABAergic cell populations that strictly maintain low activity levels in granule cells. Somatostatin-expressing cells are one of those interneuron populations, selectively targeting the distal dendrites of granule cells, where cortical multimodal information reaches the DG. Nonetheless, somatostatin cells have very low connection probability and synaptic efficacy with both granule cells and other interneuron types. Hence, the role of somatostatin cells in DG circuitry, particularly in the context of pattern separation, remains uncertain. Here, by using optogenetic stimulation and behavioral tasks in mice, we demonstrate that somatostatin cells are required for the acquisition of both contextual and spatial overlapping memories.
Asunto(s)
Giro Dentado/citología , Giro Dentado/metabolismo , Aprendizaje Discriminativo/fisiología , Memoria Episódica , Células Secretoras de Somatostatina/metabolismo , Animales , Giro Dentado/química , Femenino , Ácido Glutámico/análisis , Ácido Glutámico/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Optogenética/métodos , Somatostatina/análisis , Somatostatina/metabolismo , Células Secretoras de Somatostatina/químicaRESUMEN
Schizophrenia is a severe psychiatric disorder that results in a significant disability for the patient. The disorder is characterized by impairment of the adaptive orchestration of actions, a cognitive function that is mainly dependent on the prefrontal cortex. This behavioral deficit, together with cellular and neurophysiological alterations in the prefrontal cortex, as well as reduced density of GABAergic cells and aberrant oscillatory activity, all indicate structural and functional deficits of the prefrontal cortex in schizophrenia. Among the several risk factors for the development of schizophrenia, stress during the prenatal period has been identified as crucial. Thus, it is proposed that prenatal stress induces neurodevelopmental alterations in the prefrontal cortex that are expressed as cognitive impairment observed in schizophrenia. However, the precise mechanisms that link prenatal stress with the impairment of prefrontal cortex function is largely unknown. Reelin is an extracellular matrix protein involved in the development of cortical neural connectivity at embryonic stages, and in synaptic plasticity at postnatal stages. Interestingly, down-regulation of reelin expression has been associated with epigenetic changes in the reelin gene of the prefrontal cortex of schizophrenic patients. We recently showed that, similar to schizophrenic patients, prenatal stress induces down-expression of reelin associated with the methylation of its promoter in the rodent prefrontal cortex. These alterations were paralleled with altered prefrontal cortex functional connectivity and impairment in prefrontal cortex-dependent behavioral tasks. Therefore, considering molecular, cellular, physiological and behavioral evidence, we propose a unifying framework that links prenatal stress and prefrontal malfunction through epigenetic alterations of the reelin gene.
Asunto(s)
Encéfalo/embriología , Moléculas de Adhesión Celular Neuronal/genética , Epigénesis Genética/fisiología , Proteínas de la Matriz Extracelular/genética , Proteínas del Tejido Nervioso/genética , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Esquizofrenia/etiología , Esquizofrenia/fisiopatología , Serina Endopeptidasas/genética , Estrés Fisiológico/fisiología , Encéfalo/fisiopatología , Trastornos del Conocimiento/fisiopatología , Metilación de ADN , Femenino , Expresión Génica , Humanos , Embarazo , Proteína Reelina , Factores de Riesgo , Trastorno de la Conducta Social/fisiopatologíaRESUMEN
Neuronal ensembles are crucial for episodic memory and spatial mapping. Sleep, particularly non-REM (NREM), is vital for memory consolidation, as it triggers plasticity mechanisms through brain oscillations that reactivate neuronal ensembles. Here, we assessed their role in consolidating hippocampal spatial representations during sleep. We recorded hippocampus activity in rats performing a spatial object-place recognition (OPR) memory task, during encoding and retrieval periods, separated by intervening sleep. Successful OPR retrieval correlated with NREM duration, during which cortical oscillations decreased in power and density as well as neuronal spiking, suggesting global downregulation of network excitability. However, neurons encoding specific spatial locations (i.e., place cells) or objects during OPR showed stronger synchrony with brain oscillations compared to non-encoding neurons, and the stability of spatial representations decreased proportionally with NREM duration. Our findings suggest that NREM sleep may promote flexible remapping in hippocampal ensembles, potentially aiding memory consolidation and adaptation to novel spatial contexts.
RESUMEN
Rodents establish dominance hierarchy as a social ranking system in which one subject acts as dominant over all the other subordinate individuals. Dominance hierarchy regulates food access and mating opportunities, but little is known about its significance in other social behaviors, for instance during collective navigation for foraging or migration. Here, we implemented a simplified goal-directed spatial task in mice, in which animals navigated individually or collectively with their littermates foraging for food. We compared between conditions and found that the social condition exerts significant influence on individual displacement patterns, even when efficient navigation rules leading to reward had been previously learned. Thus, movement patterns and consequent task performance were strongly dependent on contingent social interactions arising during collective displacement, yet their influence on individual behavior was determined by dominance hierarchy. Dominant animals did not behave as leaders during collective displacement; conversely, they were most sensitive to the social environment adjusting their performance accordingly. Social ranking in turn was associated with specific spontaneous neural activity patterns in the prefrontal cortex and hippocampus, with dominant mice showing higher firing rates, larger ripple oscillations, and stronger neuronal entrainment by ripples than subordinate animals. Moreover, dominant animals selectively increased their cortical spiking activity during collective movement, while subordinate mice did not modify their firing rates, consistent with dominant animals being more sensitive to the social context. These results suggest that dominance hierarchy influences behavioral performance during contingent social interactions, likely supported by the coordinated activity in the hippocampal-prefrontal circuit.
RESUMEN
The basal forebrain delivers extensive axonal projections to the cortical mantle regulating brain states and cognitive processing. Recent evidence has established the basal forebrain as a subcortical node of the default mode network that directionally influences cortical dynamics trough gamma oscillations, yet their synaptic origin has not been established. Here, we used optogenetic stimulation and in vivo recordings of transgenic mice to show that somatostatin neurons exert an anatomically specialized role in the coordination of subcortical gamma oscillations of the rostral basal forebrain. Indeed, the spike timing of somatostatin cells was tightly correlated with gamma oscillations in the ventral pallidum, but not in the medial septum. Consequently, optogenetic inactivation of somatostatin neurons selectively disrupted the amplitude and coupling of gamma oscillations only in the ventral pallidum. Moreover, photosupression of somatostatin cells produced specific behavioral interferences, with the ventral pallidum regulating locomotor speed and the medial septum modulating spatial working memory. Altogether, these data suggest that basal forebrain somatostatin cells can selectively synchronize local neuronal networks in the gamma band directly impinging on cortical dynamics and behavioral performance. This further supports the role of the basal forebrain as a subcortical switch commanding transitions between internally and externally oriented brain states.
Asunto(s)
Prosencéfalo Basal/metabolismo , Cognición , Ritmo Gamma , Actividad Motora , Neuronas/metabolismo , Somatostatina/metabolismo , Animales , Prosencéfalo Basal/citología , Ratones , Ratones Transgénicos , Neuronas/citología , Somatostatina/genéticaRESUMEN
The midline thalamus is reciprocally connected with the medial temporal lobe, where neural circuitry essential for spatial navigation and memory formation resides. Yet, little information is available on the dynamic relationship between activity patterns in the midline thalamus and medial temporal lobe. Here, we report on the functional heterogeneity of anatomically-identified thalamic neurons and the differential modulation of their activity with respect to dorsal hippocampal rhythms in the anesthetized mouse. Midline thalamic neurons expressing the calcium-binding protein calretinin, irrespective of their selective co-expression of calbindin, discharged at overall low levels, did not increase their activity during hippocampal theta oscillations, and their firing rates were inhibited during hippocampal sharp wave-ripples. Conversely, thalamic neurons lacking calretinin discharged at higher rates, increased their activity during hippocampal theta waves, but remained unaffected during sharp wave-ripples. Our results indicate that the midline thalamic system comprises at least two different classes of thalamic projection neuron, which can be partly defined by their differential engagement by hippocampal pathways during specific network oscillations that accompany distinct behavioral contexts. Thus, different midline thalamic neuronal populations might be selectively recruited to support distinct stages of memory processing, consistent with the thalamus being pivotal in the dialogue of cortical circuits.
Asunto(s)
Hipocampo/fisiología , Red Nerviosa/fisiología , Neuronas/fisiología , Lóbulo Temporal/fisiología , Tálamo/fisiología , Potenciales de Acción/fisiología , Animales , Calbindina 2/metabolismo , Calbindinas/metabolismo , Hipocampo/anatomía & histología , Memoria/fisiología , Ratones Endogámicos C57BL , Vías Nerviosas/fisiología , Neuronas/metabolismo , Lóbulo Temporal/anatomía & histología , Tálamo/anatomía & histologíaRESUMEN
Prenatal stress causes predisposition to cognitive and emotional disturbances and is a risk factor towards the development of neuropsychiatric conditions like depression, bipolar disorders and schizophrenia. The extracellular protein Reelin, expressed by Cajal-Retzius cells during cortical development, plays critical roles on cortical lamination and synaptic maturation, and its deregulation has been associated with maladaptive conditions. In the present study, we address the effect of prenatal restraint stress (PNS) upon Reelin expression and signaling in pregnant rats during the last 10 days of pregnancy. Animals from one group, including control and PNS exposed fetuses, were sacrificed and analyzed using immunohistochemical, biochemical, cell biology and molecular biology approaches. We scored changes in the expression of Reelin, its signaling pathway and in the methylation of its promoter. A second group included control and PNS exposed animals maintained until young adulthood for behavioral studies. Using the optical dissector, we show decreased numbers of Reelin-positive neurons in cortical layer I of PNS exposed animals. In addition, neurons from PNS exposed animals display decreased Reelin expression that is paralleled by changes in components of the Reelin-signaling cascade, both in vivo and in vitro. Furthermore, PNS induced changes in the DNA methylation levels of the Reelin promoter in culture and in histological samples. PNS adult rats display excessive spontaneous locomotor activity, high anxiety levels and problems of learning and memory consolidation. No significant visuo-spatial memory impairment was detected on the Morris water maze. These results highlight the effects of prenatal stress on the Cajal-Retzius neuronal population, and the persistence of behavioral consequences using this treatment in adults, thereby supporting a relevant role of PNS in the genesis of neuropsychiatric diseases. We also propose an in vitro model that can yield new insights on the molecular mechanisms behind the effects of prenatal stress.
Asunto(s)
Moléculas de Adhesión Celular Neuronal/genética , Metilación de ADN , Proteínas de la Matriz Extracelular/genética , Exposición Materna , Trastornos Mentales/etiología , Proteínas del Tejido Nervioso/genética , Efectos Tardíos de la Exposición Prenatal , Regiones Promotoras Genéticas , Serina Endopeptidasas/genética , Estrés Fisiológico , Estrés Psicológico , Animales , Animales Recién Nacidos , Antígenos Nucleares/genética , Antígenos Nucleares/metabolismo , Conducta Animal , Moléculas de Adhesión Celular Neuronal/metabolismo , Corteza Cerebral/metabolismo , Quinasa 5 Dependiente de la Ciclina/metabolismo , Modelos Animales de Enfermedad , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Embarazo , Ratas , Proteína Reelina , Serina Endopeptidasas/metabolismo , Transducción de SeñalRESUMEN
Schizophrenia is a severe psychiatric disorder that results in a significant disability for the patient. The disorder is characterized by impairment of the adaptive orchestration of actions, a cognitive function that is mainly dependent on the prefrontal cortex. This behavioral deficit, together with cellular and neurophysiological alterations in the prefrontal cortex, as well as reduced density of GABAergic cells and aberrant oscillatory activity, all indicate structural and functional deficits of the prefrontal cortex in schizophrenia. Among the several risk factors for the development of schizophrenia, stress during the prenatal period has been identified as crucial. Thus, it is proposed that prenatal stress induces neurodevelopmental alterations in the prefrontal cortex that are expressed as cognitive impairment observed in schizophrenia. However, the precise mechanisms that link prenatal stress with the impairment of prefrontal cortex function is largely unknown. Reelin is an extracellular matrix protein involved in the development of cortical neural connectivity at embryonic stages, and in synaptic plasticity at postnatal stages. Interestingly, down-regulation of reelin expression has been associated with epigenetic changes in the reelin gene of the prefrontal cortex of schizophrenic patients. We recently showed that, similar to schizophrenic patients, prenatal stress induces down-expression of reelin associated with the methylation of its promoter in the rodent prefrontal cortex. These alterations were paralleled with altered prefrontal cortex functional connectivity and impairment in prefrontal cortex-dependent behavioral tasks. Therefore, considering molecular, cellular, physiological and behavioral evidence, we propose a unifying framework that links prenatal stress and prefrontal malfunction through epigenetic alterations of the reelin gene.