Age-related Changes in Lateral Entorhinal and CA3 Neuron Allocation Predict Poor Performance on Object Discrimination

Abstract

Age-related memory deficits correlate with dysfunction in the CA3 subregion of the hippocampus, which includes both hyperactivity and overly rigid activity patterns. While changes in intrinsic membrane currents and interneuron alterations are involved in this process, it is not known whether alterations in afferent input to CA3 also contribute. Neurons in layer II of the lateral entorhinal cortex (LEC) project directly to CA3 through the perforant path, but no data are available regarding the effects of advanced age on LEC activity and whether these activity patterns update in response to environmental change. Furthermore, it is not known the extent to which age-related deficits in sensory discrimination relate to the inability of aged CA3 neurons to update in response to new environments. Young and aged rats were pre-characterized on a LEGO© object discrimination task, comparable to behavioral tests in humans in which CA3 hyperactivity has been linked to impairments. The cellular compartment analysis of temporal activity with fluorescence in situ hybridization for the immediate-early gene Arc was then used to identify the principal cell populations that were active during two distinct epochs of random foraging in different environments. This approach enabled the extent to which rats could discriminate two similar objects to be related to the ability of CA3 neurons to update across different environments. In both young and aged rats, there were animals that performed poorly on the LEGO object discrimination task. In the aged rats only, however, the poor performers had a higher percent of CA3 neurons that were active during random foraging in a novel environment, but this is not related to the ability of CA3 neurons to remap when the environment changed. Afferent neurons to CA3 in LEC, as identified with the retrograde tracer choleratoxin B (CTB), also showed a higher percentage of cells that were positive for Arc mRNA in aged poor performing rats. This suggests that LEC contributes to the hyperactivity seen in CA3 of aged animals with object discrimination deficits and age-related cognitive decline may be the consequence of dysfunction endemic to the larger network.

Age and ketogenic diet have dissociable effects on synapse-related gene expression between hippocampal subregions

“…Indeed, the age-related vulnerability of CA3 neurons is a well-documented phenomenon. The data presented here are consistent with alterations in CA3 excitability observed in humans (Yassa et al, 2010(Yassa et al, , 2011, monkeys (Thomé et al, 2015), and rats (Maurer et al, 2017;Robitsek et al, 2015;Wilson, 2005). Additionally, changes in gene expression specifically within CA3, and not DG, correlate with cognitive outcomes in aged rats (Haberman et al, 2011).…”

Integrating new findings and examining clinical applications of pattern separation

“…Convergent data across animal and human studies have suggested that a key neural substrate for this decline is a shift in hippocampal network dynamics away from pattern separation and toward pattern com- pletion 72 , which appears to be mediated by CA3 hyperactivity 35,73–76 and representational rigidity 35,72,75,77 —a failure to remap or manifest a novelty signal when stimuli are similar but not identical. These alterations may be closely linked to changes in the perforant path 78–81 and to disinhibition in the DG and CA3 subregions resulting from the loss of inhibitory tone in GABAergic interneurons 72,82 .…”

“…These changes in excitation/inhibition balance in hippocampal circuitry may act to strengthen CA3’s recurrent collaterals, potentially biasing the network toward reactivation of prior experiences (that is, pattern completion) at the expense of learning new information 71,72 . A recent study found that the LEC contributes to CA3 hyperactivity in aged rats with object-discrimination deficits 76 . However, studies have reported that hippocampal activity is eventually reduced during memory task performance in those with mild AD 83,84 .…”

Experience-dependent effects of muscimol-induced hippocampal excitation on mnemonic discrimination

“…FISH for Arc mRNA was carried out as previously described (Guzowski et al, 1999;Guzowski and Worley, 2001;Burke et al, 2012;Hernandez et al, 2017Hernandez et al, , 2018Maurer et al, 2017). Briefly, digoxigenin (DIG)-labeled riboprobes were generated with a commercial Stitched low magnification flyover images were collected by fluorescence microscopy (Keyence) with a 2X objective.…”

“…In Exps.1 and 2, object discrimination tasks were carried out in an L-shaped maze bounded by a start area and choice platform, as previously described ( Fig.2A; Johnson et al, 2017;Maurer et al, 2017). Procedures for shaping and object discrimination training were identical to those described previously .…”