Perforant Path Fiber Loss Results in Mnemonic Discrimination Task Deficits in Young Rats

Abstract

The observation that entorhinal input to the hippocampus declines in old age is well established across human studies and in animal models. This loss of perforant path fibers is exaggerated in individuals with episodic memory deficits and Mild Cognitive Impairment, suggesting that perforant path integrity is associated with progression to Alzheimer’s Disease. During normal aging, behaviors that measure the ability of a study participant to discriminate between stimuli that share features is particularly sensitive to perforant fiber loss. Evidence linking perforant path changes to cognitive decline, however, has been largely correlational. Thus, the current study tested the causative role of perforant path fiber loss in behavioral decline by performing a unilateral knife cut to disconnect the entorhinal cortex from the hippocampus in the right hemisphere in young male and female rats. This approach does not completely disconnect the hippocampus from the entorhinal cortex but rather reduces the effective connectivity between these two structures. Male and female rats were then tested on the rodent variant of the mnemonic discrimination task, which is believed to critically rely on perforant path fiber integrity. Right hemisphere perforant path transections produced a significant impairment in the abilities of lesioned animals to discriminate between objects with high levels of feature overlap. This deficit was not observed in the male and female sham groups that received a cut to cortex above the white matter. Together these data support the view that, across species, age-related perforant path fiber loss produces behavioral deficits in the ability to discriminate between stimuli with perceptual overlap.

Rodent mnemonic similarity task performance requires the prefrontal cortex

“…Tasks were carried out in a U-shaped maze built on a low table (surface 148 cm x 76 cm) out of plastic building bricks (DUPLO®, LEGO®, Enfield, CT; Fig.1A), similar to mazes previously used in our laboratory (Hernandez et al, 2015(Hernandez et al, , 2017Johnson et al, 2017;Maurer et al, 2017;Burke et al, 2018b;Hernandez et al, 2018a;Johnson et al, 2018;Kreher et al, 2019). Rats were trained in daily sessions to alternate between a designated start area in one arm and choice platform in the opposite arm ( Fig.1A) by providing food reward in each location.…”

“…After reaching criterion of ≥81.3% correct responses on 2 consecutive training sessions, rats were given 2 days off before their first mnemonic discrimination test. Tests were carried out as previously described with the learned target and a set of lures that shared 0-90% feature overlap (Fig.1C) (Johnson et al, 2017;Burke et al, 2018b;Johnson et al, 2018). Each session consisted of 50 trials: 10 with an entirely distinct standard lure (frog figurine, 0% overlap), 10 with each of 3 perceptually similar LEGO lure objects, sharing 50, 70, and 90% feature overlap, and 10 with an identical copy of the target object.…”

“…Previous studies (Hernandez et al, 2015(Hernandez et al, , 2017Johnson et al, 2017;Burke et al, 2018b;Johnson et al, 2018) have found that rats default to selecting an object on a particular side (regardless of features) when learning forced-choice discrimination tasks. This side-biased strategy is particularly prominent in aged rats (Hernandez et al 2015;Johnson et al 2017) and young adult rats in which connectivity across perirhinal cortex, hippocampus, and/or the prefrontal cortex is experimentally disrupted (Lee and Solivan, 2008;Lee, 2010a, 2010b;Hernandez et al, 2017;Burke et al, 2018b;Johnson et al, 2018). To determine if this was the case in the current study, side bias indices were calculated as the absolute value of (total number of left well responses -total number of right well responses) / total number trials.…”

“…To determine if this speeding of test completion was attributable to faster response selection, response latencies were scored on video recordings of each test session. As in prior studies (Johnson et al, 2017;Burke et al, 2018b;Johnson et al, 2018), response latencies are defined as the time elapsed between the point at which the rat's nose crossed the threshold of the choice platform and the point at which the rat initiated displacement of one of the objects on the choice platform. Response latencies for correct responses to rats' inherent biased side are shown in Figure 5C.…”

“…Specifically, infusions of the GABA A agonist muscimol in CA3/DG impaired discrimination in a first block of tests when lure objects were novel, but not on subsequent second and third blocks of tests as lures became familiar (Johnson et al, 2018). In contrast, interference with perforant path input to the hippocampus impaired mnemonic discrimination performance across multiple tests (Burke et al, 2018b). These findings raised two points of interest.…”