RESUMO
Alzheimer's disease (AD) is a severe neurodegenerative disorder and the most common form of dementia in elderly individuals, characterized by memory deficits, cognitive decline, and neuropathology. The identification of preclinical markers for AD remains elusive. We employed an ultrasound-evoked spatial memory assay to investigate path integration (PI) in wild type C57BL/6â¯J and 5xFAD mice. We observed significant recruitment of the mammillary bodies (MB) and subiculum (Sub) - core regions of the Papez circuit during PI, as indicated by increased expression of the immediate early gene c-Fos in C57BL/6â¯J mice. In 5xFAD mice, amyloid-beta (Aß) vulnerability in the MB and Sub was evident at 3-months of age, preceding widespread pathology at 5-months of age. In parallel, we detected significant behavioral deficits in PI in the 5XFAD mice at 5- but not 3-months of age. Sex based analysis revealed a more profound deficit in males compared to females at 5-months of age. Our data suggest PI may be as an early indicator of AD, potentially associated with dysfunction within the Papez circuit.
Assuntos
Doença de Alzheimer , Encéfalo , Humanos , Masculino , Feminino , Camundongos , Animais , Idoso , Lactente , Camundongos Transgênicos , Encéfalo/metabolismo , Camundongos Endogâmicos C57BL , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Modelos Animais de DoençasRESUMO
Associating contexts with rewards depends on hippocampal circuits, with local inhibitory interneurons positioned to play an important role in shaping activity. Here, we demonstrate that the encoding of context-reward memory requires a ventral hippocampus (vHPC) to nucleus accumbens (NAc) circuit that is gated by cholecystokinin (CCK) interneurons. In a sucrose conditioned place preference (CPP) task, optogenetically inhibiting vHPC-NAc terminals impaired the acquisition of place preference. Transsynaptic rabies tracing revealed vHPC-NAc neurons were monosynaptically innervated by CCK interneurons. Using intersectional genetic targeting of CCK interneurons, ex vivo optogenetic activation of CCK interneurons increased GABAergic transmission onto vHPC-NAc neurons, while in vivo optogenetic inhibition of CCK interneurons increased cFos in these projection neurons. Notably, CCK interneuron inhibition during sucrose CPP learning increased time spent in the sucrose-associated location, suggesting enhanced place-reward memory. Our findings reveal a previously unknown hippocampal microcircuit crucial for modulating the strength of contextual reward learning.