RESUMO
Precise information flow during mnemonic and executive tasks requires the coactivation of adult prefrontal and hippocampal networks in oscillatory rhythms. This interplay emerges early in life, most likely as an anticipatory template of later cognitive performance. At neonatal age, hippocampal theta bursts drive the generation of prefrontal theta-gamma oscillations. In the absence of direct reciprocal interactions, the question arises of which feedback mechanisms control the early entrainment of prefrontal-hippocampal networks. Here, we demonstrate that prefrontal-hippocampal activity couples with discontinuous theta oscillations and neuronal firing in both lateral entorhinal cortex and ventral midline thalamic nuclei of neonatal rats. However, these two brain areas have different contributions to the neonatal long-range communication. The entorhinal cortex mainly modulates the hippocampal activity via direct axonal projections. In contrast, thalamic theta bursts are controlled by the prefrontal cortex via mutual projections and contribute to hippocampal activity. Thus, the neonatal prefrontal cortex modulates the level of hippocampal activation by directed interactions with the ventral midline thalamus. Similar to the adult task-related communication, theta-band activity ensures the feedback control of long-range coupling in the developing brain. SIGNIFICANCE STATEMENT: Memories are encoded by finely tuned interactions within large-scale neuronal networks. This cognitive performance is not inherited, but progressively matures in relationship with the establishment of long-range coupling in the immature brain. The hippocampus initiates and unidirectionally drives the oscillatory entrainment of neonatal prefrontal cortex, yet feedback interactions that precisely control this early communication are still unresolved. Here, we identified distinct roles of entorhinal cortex and ventral midline thalamus for the functional development of prefrontal-hippocampal interactions. While entorhinal oscillations modulate the hippocampal activity by timing the neuronal firing via monosynaptic afferents, thalamic nuclei act as a relay station routing prefrontal activation back to hippocampus. Understanding the mechanisms of network maturation represents the prerequisite for assessing circuit dysfunction in neurodevelopmental disorders.
Assuntos
Mapeamento Encefálico , Córtex Entorrinal/fisiologia , Hipocampo/fisiologia , Vias Neurais/fisiologia , Córtex Pré-Frontal/fisiologia , Tálamo/fisiologia , Potenciais de Ação , Análise de Variância , Animais , Animais Recém-Nascidos , Masculino , Neurônios/fisiologia , Córtex Pré-Frontal/lesões , Ratos , Ratos Wistar , Estilbamidinas/metabolismo , Tálamo/lesões , Fatores de TempoRESUMO
Mnemonic and executive performance is encoded into activity patterns of complex neuronal networks. Lesion studies revealed that adult recognition memory critically depends on the activation of the prefrontal cortex (PFC) and hippocampus (HP). However, its developmental profile remains poorly elucidated. We previously showed the rat PFC and HP are functionally coupled in theta- and gamma-band oscillations during neonatal [postnatal day (P) 5-8] and pre-juvenile (P10-15) stages of development. Here, we assess the behavioral readout of this early prefrontal-hippocampal activation by investigating the ontogeny and the mechanisms of novelty detection and recognition memory in relationship to the functional integrity of the PFC and HP. Excitotoxic lesion of the HP at birth led to abnormal oscillatory entrainment of the PFC throughout neonatal and pre-juvenile development. Although the onset of novelty detection correlated rather with the maturation of sensory perception and motor skills than with hippocampal integrity, the pre-juvenile performance in item, spatial and temporal order recognition memory significantly decreased after HP lesion at birth. This poorer performance does result neither from abnormal developmental milestones and locomotion nor from increased anxiety. Thus, novelty recognition in rat emerges during the second postnatal week and requires functional integrity of communication within neuronal networks including the PFC and HP.
Assuntos
Comportamento Exploratório/fisiologia , Hipocampo/fisiologia , Córtex Pré-Frontal/crescimento & desenvolvimento , Reconhecimento Psicológico/fisiologia , Animais , Animais Recém-Nascidos , Ondas Encefálicas/efeitos dos fármacos , Ondas Encefálicas/fisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , N-Metilaspartato/farmacologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Ratos , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
In humans, genetic variants of DLGAP1-4 have been linked with neuropsychiatric conditions, including autism spectrum disorder (ASD). While these findings implicate the encoded postsynaptic proteins, SAPAP1-4, in the etiology of neuropsychiatric conditions, underlying neurobiological mechanisms are unknown. To assess the contribution of SAPAP4 to these disorders, we characterized SAPAP4-deficient mice. Our study reveals that the loss of SAPAP4 triggers profound behavioural abnormalities, including cognitive deficits combined with impaired vocal communication and social interaction, phenotypes reminiscent of ASD in humans. These behavioural alterations of SAPAP4-deficient mice are associated with dramatic changes in synapse morphology, function and plasticity, indicating that SAPAP4 is critical for the development of functional neuronal networks and that mutations in the corresponding human gene, DLGAP4, may cause deficits in social and cognitive functioning relevant to ASD-like neurodevelopmental disorders.
Assuntos
Transtorno do Espectro Autista/genética , Disfunção Cognitiva/genética , Proteínas do Tecido Nervoso/genética , Proteínas Associadas SAP90-PSD95/genética , Animais , Comportamento Animal , Modelos Animais de Doenças , Feminino , Relações Interpessoais , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Comportamento Social , Sinapses/metabolismoRESUMO
We compared the dynamics of hippocampal and prefrontal interactions in rats as they used spatial contexts to guide the retrieval of object memories. Functional connectivity analysis indicated a flow of contextual information from the hippocampus to prefrontal cortex upon the rat's entry into the spatial context. Conversely, upon the onset of object sampling, the direction of information flow reversed, consistent with prefrontal control over the retrieval of context-appropriate hippocampal memory representations.
Assuntos
Comportamento Animal/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Rede Nervosa/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Masculino , Neurônios/fisiologia , Ratos Long-Evans , RecompensaRESUMO
High-prevalence/low-severity cognitive deficits represent the life-long burden of a perinatal hypoxicischemic (HI) insult. They have been proposed to result from dysmaturation of prelimbic-hippocampal networks, which account for mnemonic and executive performance. Already at neonatal age the communication within these networks is largely reduced after an early HI insult with mild/moderate structural outcome. However, the longlasting consequences of the neonatal network dysfunction remain unknown. Here,we combine MRI and electrophysiology in vivo with behavioral testing to assess the effects of an early HI insult on the structure and function of prelimbic-hippocampal networks and on related cognitive abilities of juvenile rats. Despite the absence of lesions over the prelimbic cortex (PL) and hippocampus (HP), juvenile rats experiencing an early HI have lower performance in item and temporal order recognition memory. These cognitive deficits do not result from delayed somatic development or increased locomotion or anxiety. More likely, abnormal activity patterns and interactions within prelimbic-hippocampal networks account for behavioral impairment. The early HI insult causes power reduction of the fast (1248 Hz) network activity and diminishment of neuronal firing in the PL and HP. This weaker entrainment of local circuits at juvenile age emerges in the absence of sufficiently strong directed interactions within neonatal prelimbic-hippocampal networks. Similar developmental mechanisms may account for poorer academic achievements of HI-injured infants.
Assuntos
Deficiências do Desenvolvimento/etiologia , Hipocampo/patologia , Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/patologia , Transtornos da Memória/etiologia , Córtex Pré-Frontal/patologia , Fatores Etários , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Potenciais Evocados/fisiologia , Comportamento Exploratório/fisiologia , Feminino , Membro Anterior/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Força Muscular/fisiologia , Vias Neurais/patologia , Gravidez , Ratos , Reconhecimento Psicológico/fisiologia , Reflexo , Estatísticas não ParamétricasRESUMO
Due to improved survival rates and outcome of human infants experiencing a hypoxic-ischemic episode, cognitive dysfunctions have become prominent. They might result from abnormal communication within prefrontal-hippocampal networks, as synchrony and directed interactions between the prefrontal cortex and hippocampus account for mnemonic and executive performance. Here, we elucidate the structural and functional impact of hypoxic-ischemic events on developing prefrontal-hippocampal networks in an immature rat model of injury. The magnitude of infarction, cell loss and astrogliosis revealed that an early hypoxic-ischemic episode had either a severe or a mild/moderate outcome. Without affecting the gross morphology, hypoxia-ischemia with mild/moderate outcome diminished prefrontal neuronal firing and gamma network entrainment. This dysfunction resulted from decreased coupling synchrony within prefrontal-hippocampal networks and disruption of hippocampal theta drive. Thus, early hypoxia-ischemia may alter the functional maturation of neuronal networks involved in cognitive processing by disturbing the communication between the neonatal prefrontal cortex and hippocampus.
Assuntos
Ondas Encefálicas , Hipocampo/patologia , Hipóxia-Isquemia Encefálica/patologia , Vias Neurais/patologia , Neurônios/patologia , Córtex Pré-Frontal/patologia , Animais , Animais Recém-Nascidos , Comportamento Animal , Cognição , Imagem de Tensor de Difusão , Hipocampo/fisiopatologia , Humanos , Hipóxia-Isquemia Encefálica/fisiopatologia , Masculino , Vias Neurais/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Ratos , Ratos Wistar , ReflexoRESUMO
The coactivation of prefrontal and hippocampal networks in oscillatory rhythms is critical for precise information flow in mnemonic and executive tasks, yet the mechanisms governing its development are still unknown. Here, we demonstrate that already in neonatal rats, patterns of discontinuous oscillatory activity precisely entrain the firing of prefrontal neurons and have distinct spatial and temporal organization over cingulate and prelimbic cortices. Moreover, we show that hippocampal theta bursts drive the generation of neonatal prefrontal oscillations by phase-locking the neuronal firing via axonal pathways. Consequently, functional impairment of the hippocampus reduces the prefrontal activity. With ongoing maturation continuous theta-gamma oscillations emerge and mutually entrain the prejuvenile prefrontal-hippocampal networks. Thus, theta-modulated communication within developing prefrontal-hippocampal networks may be relevant for circuitry refinement and maturation of functional units underlying information storage at adulthood.