The hippocampal physiology of approaching middle‐age: Early indicators of change

Abstract

Age-related cognitive decline presents serious lifestyle challenges, and anatomical changes to the hippocampus are often implicated in clinical conditions later in life. However, relatively little is known about how hippocampal physiology is altered in the transition to middle-age, when early detection may offer the best opportunity for successful treatment. High-yield extracellular recording is a powerful tool for understanding brain function in freely moving animals at single-cell resolution and with millisecond precision. We used this technique to characterize changes to hippocampal physiology associated with maturation in 35-week-old rats. Combining a series of behavioral tasks with recordings of large numbers of neurons, local field potentials (LFP), and network patterns of activation, we were able to generate a comprehensive picture based on more than 25 different assays for each subject. Notable changes associated with aging included increased firing rates in interneurons, reduced LFP power but increased frequency in the 4-12 Hz theta band, and impairment in hippocampal pattern-separation for different environments. General properties of pyramidal cell firing and spatial map integrity were preserved. There was no impairment in theta phase-precession, experience-dependent place field expansion, or sleep reactivation of waking network patterns. There were however changes in foraging strategy and behavioral responses to the introduction of a novel environment. Taken together the results reveal a diverse pattern of changes which are of increasing relevance in an aging population. They also highlight areas where high-yield electrophysiological assays can be used to provide the sensitivity and throughput required for pre-clinical drug-discovery programs.

Age-related changes in place learning for adjacent and separate locations

“…Thus, interventions that increase neurogenesis during adulthood may have clinical implications for reversing age-related impairments in pattern separation and associated DG dysfunction (Sahay et al, 2011). The development of such interventions may be particularly important given recent evidence in animals suggesting that pattern separation deficits may begin in middle age (Huxter et al, 2012). Creer et al (2010) reported that voluntary running improved the ability of adult mice to discriminate between two spatially adjacent locations, suggesting an improvement in spatial pattern separation.…”

“…As reviewed previously, pattern separation has been suggested to become less efficient in old age. However, recent evidence suggests that pattern separation deficits may begin in middle age (Huxter et al, 2012). Therefore, future longitudinal studies are needed to examine how pattern separation efficiency changes between middle-age and old-age.…”

Sleep, Cognition, and Normal Aging

“…If so, then the loss of memory consolidation during sleep might be one reason for the weakening evidence for sleep—cognition associations in older adults: If active cognitive processes are not occurring during sleep then sleep variables would not be expected to correlate with cognitive variables (Tables 3–6). Indeed, in animal studies, both young rodents and “ middle-aged ” rodents tend to show “replay” of memories during sleep (i.e., reactivation of learned hippocampal sequences; Huxter, Miranda, & Dias, 2012), but sleep-dependent memory replay is diminished in older rodents (Gerrard, Burke, McNaughton, & Barnes, 2008). Behavioral evidence from animal models also supports the idea of an age-related decline in memory consolidation (e.g., Hermann et al, 2007; Oler & Markus, 1998; Ward, Oler, & Markus, 1999) In the following section, we address whether there is an age-related change in sleep-dependent procedural memory (Table 7) and episodic memory (Table 8) consolidation in aging humans.…”

Peer Review #1 of "CA1 pyramidal cells have diverse biophysical properties, affected by development, experience, and aging (v0.1)"

“…4). Place fields increase in size with increasing exploration [209][210][211]. Place field expansion occurs on the first day of multiple runs through an environment, but not on subsequent days [212].…”

“…Place field expansion occurs on the first day of multiple runs through an environment, but not on subsequent days [212]. Firing rates within place fields also increase and the center of mass of the firing rate distribution shifts backwards in space [209][210][211][212].…”