Spread of pathological human Tau from neurons to oligodendrocytes and loss of high-firing pyramidal neurons in aging mice.

Intracellular aggregation of hyperphosphorylated Tau (pTau) in the brain is associated with cognitive and motor impairments, and ultimately neurodegeneration. We investigate how human pTau affects cells and network activity in the hippocampal formation of the THY-Tau22 tauopathy model mice in vivo. We find that pTau preferentially accumulates in deep-layer pyramidal neurons, leading to neurodegeneration, and we establish that pTau spreads to oligodendrocytes. During goal-directed virtual navigation in aged transgenic mice, we detect fewer high-firing prosubicular pyramidal cells, but the firing population retains its coupling to theta oscillations. Analysis of network oscillations and firing patterns of pyramidal and GABAergic neurons recorded in head-fixed and freely moving mice suggests preserved neuronal coordination. In spatial memory tests, transgenic mice have reduced short-term familiarity, but spatial working and reference memory are surprisingly normal. We hypothesize that unimpaired subcortical network mechanisms maintain cortical neuronal coordination, counteracting the widespread pTau aggregation, loss of high-firing cells, and neurodegeneration.

Unexpected Rule-Changes in a Working Memory Task Shape the Firing of Histologically Identified Delay-Tuned Neurons in the Prefrontal Cortex.

Working memory-guided behaviors require memory retention during delay periods, when subsets of prefrontal neurons have been reported to exhibit persistently elevated firing. What happens to delay activity when information stored in working memory is no longer relevant for guiding behavior? In this study, we perform juxtacellular recording and labeling of delay-tuned (-elevated or -suppressed) neurons in the prelimbic cortex of freely moving rats, performing a familiar delayed cue-matching-to-place task. Unexpectedly, novel task-rules are introduced, rendering information held in working memory irrelevant. Following successful strategy switching within one session, delay-tuned neurons are filled with neurobiotin for histological analysis. Delay-elevated neurons include pyramidal cells with large heterogeneity of soma-dendritic distribution, molecular expression profiles, and task-relevant activity. Rule change induces heterogenous adjustments on individual neurons and ensembles' activity but cumulates in balanced firing rate reorganizations across cortical layers. Our results demonstrate divergent cellular and network dynamics when an abrupt change in task rules interferes with working memory.

Divisions of Identified Parvalbumin-Expressing Basket Cells during Working Memory-Guided Decision Making.

Parvalbumin-expressing basket cells tightly control cortical networks and fire remarkably stereotyped during network oscillations and simple behaviors. How can these cells support multifaceted situations with different behavioral options and complex temporal sequences? We recorded from identified parvalbumin-expressing basket cells in prefrontal cortex of freely moving rats performing a multidimensional delayed cue-matching-to-place task, juxtacellularly filled recorded neurons for unequivocal histological identification, and determined their activity during temporally structured task episodes, associative working-memory, and stimulus-guided choice behavior. We show that parvalbumin-expressing basket cells do not fire homogenously, but individual cells were recruited or inhibited during different task episodes. Firing of individual basket cells was correlated with amount of presynaptic VIP (vasoactive intestinal polypeptide)-expressing GABAergic input. Together with subsets of pyramidal neurons, activity of basket cells differentiated for sequential actions and stimulus-guided choice behavior. Thus, interneurons of the same cell type can be recruited into different neuronal ensembles with distinct firing patterns to support multi-layered cognitive computations.

Aging, neurogenesis, and caloric restriction in different model organisms.

Brain aging is a multifactorial process that is occurring across multiple cognitive domains. A significant complaint that occurs in the elderly is a decrement in learning and memory ability. Both rodents and zebrafish exhibit a similar problem with memory during aging. The neurobiological changes that underlie this cognitive decline are complex and undoubtedly influenced by many factors. Alterations in the birth of new neurons and neuron turnover may contribute to age-related cognitive problems. Caloric restriction is the only non-genetic intervention that reliably increases life span and healthspan across multiple organisms although the molecular mechanisms are not well-understood. Recently the zebrafish has become a popular model organism for understanding the neurobiological consequences but to date very little work has been performed. Similarly, few studies have examined the effects of dietary restriction in zebrafish. Here we review the literature related to memory decline, neurogenesis, and caloric restriction across model organisms and suggest that zebrafish has the potential to be an important animal model for understanding the complex interactions between age, neurobiological changes in the brain, and dietary regimens or their mimetics as interventions.