Cognitive aging is associated with redistribution of synaptic weights in the hippocampus

Abstract

Behaviors that rely on the hippocampus are particularly susceptible to chronological aging, with many aged animals (including humans) maintaining cognition at a young adult-like level, but many others the same age showing marked impairments. It is unclear whether the ability to maintain cognition over time is attributable to brain maintenance, sufficient cognitive reserve, compensatory changes in network function, or some combination thereof. While network dysfunction within the hippocampal circuit of aged, learning-impaired animals is well-documented, its neurobiological substrates remain elusive. Here we show that the synaptic architecture of hippocampal regions CA1 and CA3 is maintained in a young adult-like state in aged rats that performed comparably to their young adult counterparts in both trace eyeblink conditioning and Morris water maze learning. In contrast, among learning-impaired, but equally aged rats, we found that a redistribution of synaptic weights amplifies the influence of autoassociational connections among CA3 pyramidal neurons, yet reduces the synaptic input onto these same neurons from the dentate gyrus. Notably, synapses within hippocampal region CA1 showed no group differences regardless of cognitive ability. Taking the data together, we find the imbalanced synaptic weights within hippocampal CA3 provide a substrate that can explain the abnormal firing characteristics of both CA3 and CA1 pyramidal neurons in aged, learning-impaired rats. Furthermore, our work provides some clarity with regard to how some animals cognitively age successfully, while others’ lifespans outlast their “mindspans.”

Differential effects of brain maintenance and cognitive reserve on age-related cognitive decline

“…The neurobiological mechanisms contributing to CR’s protective effect are an active area of study [42]. Our finding that IQ, a measure highly correlated with semantic knowledge, is associated with reduced rate of cognitive decline, combined with the common observation that semantic knowledge increases with age suggest that some aspects of CR may increase with age: accumulation of semantic knowledge may enable older adults to shift toward reliance on semantic knowledge as their general cognition declines.…”

Loss of functional heterogeneity along the CA3 transverse axis in aging

“…Enhanced inhibition in granule cells in AU rats may support sparse coding in the DG, which is essential for pattern separation. There is also a redistribution of synaptic weights between age groups, where AMPAR expression in stratum lucidum (the layer where mossy fibers make synaptic contacts with CA3) is higher in AU rats but AMPAR expression is significantly higher in stratum radiatum (the layer where CA3 makes autoassociational connections) in AI rats (Buss et al, 2021). Enhanced AMPAR expression in stratum lucidum may support increased feedforward activation of pattern separated outputs to CA3.…”

“…With respect to the evidence that aging has a greater effect on the role of the pCA3-dCA1-LEC pathway compared to the dCA3-pCA1-MEC pathway, the loss of reelin expression in LEC neurons occurs in the condition of memory impairment in both AI rats and rhesus monkeys, with relative sparing of that condition in AU animals in both species (Long et al, 2020; Stranahan et al, 2011a, 2011b). There is also a redistribution of synaptic weights between AI and AU age groups in rodents, where AMPAR expression in stratum lucidum (the layer where mossy fibers make synaptic contacts with CA3) is higher in AU rats but AMPAR expression is significantly higher in stratum radiatum (the layer where CA3 makes autoassociational connections) in AI rats (Buss et al, 2021). Enhanced AMPAR expression in stratum lucidum may support increased feedforward activation of pattern separated outputs to CA3.…”

“…There is also a redistribution of synaptic weights between age groups, where AMPAR expression in stratum lucidum (the layer where mossy fibers make synaptic contacts with CA3) is higher in AU rats but AMPAR expression is significantly higher in stratum radiatum (the layer where CA3 makes autoassociational connections) in AI rats (Buss et al, 2021). Enhanced pg.…”

LTD-inducing low frequency stimulation enhances p-Tau181 and p-Tau217 in an age-dependent manner in live rats

“…The hippocampus is one of the areas that p-Tau first appears during Braak stage II of AD (Braak et al, 2006) and this region of brain is particularly vulnerable to age-related changes (Buss et al, 2021;Driscoll et al, 2003;Ianov et al, 2017;McKiernan & Marrone, 2017;Veldsman et al, 2021). Synaptic plasticity mechanisms at excitatory glutamatergic synapses in hippocampus, including those underlying long-term depression (LTD), are neurophysiological substrates of normal learning and 6 memory function (Connor & Wang, 2016;Magee & Grienberger, 2020).…”