RESUMEN

Generalization allows for experience to flexibly guide behavior when conditions change. A basic physical unit of memory storage and expression in the brain are sparse, distributed groups of neurons known as ensembles (i.e., the engram). The infralimbic (IL) subregion of the ventral medial prefrontal cortex plays a key role in modulating conditioned defensive responses. How IL neuronal ensembles established during learning contribute to generalized responses is unknown. In this set of experiments, generalization was tested in male and female mice by presenting a novel, ambiguous, tone generalization stimulus following Pavlovian defensive (fear) conditioning. The first experiment was designed to test a role for IL in generalization using chemogenetic manipulations. Results show IL bidirectionally regulates defensive behavior. IL silencing promotes a switch in defensive state from vigilant scanning to generalized freezing, while IL stimulation reduces freezing in favor of scanning. Leveraging activity-dependent tagging technology (ArcCreERT2 x eYFP system), a neuronal ensemble, preferentially located in IL superficial layer 2/3, was associated with the generalization stimulus. Remarkably, in the identical discrete location, fewer reactivated neurons were associated with the generalization stimulus at the remote timepoint (30 days) following learning. When an IL neuronal ensemble established during learning was selectively chemogenetically silenced, generalization increased. Conversely, IL neuronal ensemble stimulation reduced generalization. Overall, these data identify a crucial role for IL in suppressing generalized responses. Further, we uncover an IL neuronal ensemble, formed during learning, functions to later attenuate the expression of generalization in the presence of ambiguous threat stimuli.

RESUMEN

Primary age-related tauopathy (PART) is characterized by aggregation of tau in the mesial temporal lobe in older individuals. High pathologic tau stage (Braak stage) or a high burden of hippocampal tau pathology has been associated with cognitive impairment in PART. However, the potential underlying mechanisms are not well understood. Cognitive impairment in many neurodegenerative diseases correlates with synaptic loss, raising the question of whether synaptic loss also occurs in PART. To address this, we investigated synaptic changes associated with tau Braak stage and high tau pathology burden in PART using synaptophysin and phospho-tau immunofluorescence. We compared 12 cases of definite PART with 6 controls and 6 Alzheimer disease cases. In this study, the hippocampal CA2 region showed loss of synaptophysin puncta and intensity in cases of PART with either a high stage (Braak IV) or a high burden of neuritic tau pathology. There was also loss of synaptophysin intensity in CA3 associated with a high stage or high burden of tau pathology. Loss of synaptophysin was present in Alzheimer disease, but the pattern appeared distinct. These novel findings suggest the presence of synaptic loss associated with either a high hippocampal tau burden or a Braak stage IV in PART.

Asunto(s)

RESUMEN

Learning is thought to involve changes in glutamate receptors at synapses, submicron structures that mediate communication between neurons in the central nervous system. Due to their small size and high density, synapses are difficult to resolve in vivo, limiting our ability to directly relate receptor dynamics to animal behavior. Here we developed a combination of computational and biological methods to overcome these challenges. First, we trained a deep-learning image-restoration algorithm that combines the advantages of ex vivo super-resolution and in vivo imaging modalities to overcome limitations specific to each optical system. When applied to in vivo images from transgenic mice expressing fluorescently labeled glutamate receptors, this restoration algorithm super-resolved synapses, enabling the tracking of behavior-associated synaptic plasticity with high spatial resolution. This method demonstrates the capabilities of image enhancement to learn from ex vivo data and imaging techniques to improve in vivo imaging resolution.

Asunto(s)

RESUMEN

Primary Age-Related Tauopathy (PART) is characterized by the aggregation of tau in the mesial temporal lobe in older individuals. High pathologic tau stage (Braak stage) or a high burden of hippocampal tau pathology have been associated with cognitive impairment in PART. However, the underlying mechanisms of cognitive impairment in PART are not well understood. Cognitive impairment in many neurodegenerative diseases correlates with synaptic loss, raising the question of whether synaptic loss occurs in PART. To address this, we investigated synaptic changes associated with tau Braak stage and a high tau pathology burden in PART using synaptophysin and phospho-tau immunofluorescence. We compared twelve cases of definite PART with six young controls and six Alzheimer's disease cases. In this study, we identified loss of synaptophysin puncta and intensity in the CA2 region of the hippocampus in cases of PART with either a high stage (Braak IV) or a high burden of neuritic tau pathology. There was also loss of synaptophysin intensity in CA3 associated with a high stage or high burden of tau pathology. Loss of synaptophysin signal was present in AD, but the pattern was distinct from that seen in PART. These novel findings suggest the presence of synaptic loss in PART associated with either a high hippocampal tau burden or a Braak stage IV. These synaptic changes raise the possibility that synaptic loss in PART could contribute to cognitive impairment, though future studies including cognitive assessments are needed to address this question.