ABSTRACT Mnemonic discrimination is critical for episodic memory and is dependent on the computational process of pattern separation, which allows the memory system to disambiguate prior memories from potentially overlapping new memories and avoid interference. Prior work with tasks such as the Mnemonic Similarity Task (MST) has demonstrated that discrimination performance is disproportionately affected by hippocampal insult. Further studies have demonstrated that the quality of initial encoding may affect subsequent discrimination performance. Taken together, these results imply that the strength of target memory representations determines discrimination performance in the MST. Here, we manipulated target memory strength by examining MST performance at delays ranging from a few minutes to seven days in three experiments with healthy young adults and a patient with hippocampal damage. Consistent with prior forgetting literature, both target recognition and lure discrimination declined with delay in controls. In the immediate delay condition, the similarity of lures to targets drove discrimination performance, with more similar lures eliciting false alarms and less similar lures eliciting correct rejections, as reflected in the lure discrimination index (LDI). This graded relationship was attenuated or absent at delays longer than one day. However, receiver operating characteristic (ROC) analyses revealed preserved discrimination across delays and target‐lure similarity levels. Similarly, the hippocampal patient was impaired relative to controls when considering LDI, but ROC‐based analysis revealed intact lure discrimination for the lowest‐similarity lures at immediate delays. Finally, we observed an inversion of the typical confidence‐accuracy relationship for lure trials at longer delays, with low‐confidence responses more likely to be correct for high‐similarity lures. Together these findings demonstrate that both the strength of target representations and the degree of lure similarity interact to drive discrimination performance.
ABSTRACT Hebbian plasticity, in particular long‐term potentiation (LTP) of excitatory synapses, is a positive feed‐back mechanism and has the potential to saturate its effects with negative consequences at both the single neuron and the circuit level. Metaplasticity is one of the mechanisms that can help overcome this problem. During one form of metaplasticity, a high (or low) level of neuronal activity impedes (or favors) the expression of future LTP. Although much is known about the role of synaptic activity in driving this metaplasticity effect, the specific role of postsynaptic action potential (AP) firing activity is still controversial and largely unknown. Experimentally, a high level of AP firing has resulted in either the suppression (a pro‐homeostatic effect) or the enhancement (an anti‐homeostatic effect) of a later induced LTP. Accordingly, we tested a wide range of AP firing frequencies generated by postsynaptic current pulses at different time intervals relative to the time of LTP induction at Schaffer collateral synapses of hippocampal CA1 neurons in Sprague–Dawley rats. We found that a wide range of AP firing frequencies, from 3 to 90 Hz, consistently inhibited the expression of future LTP at all time intervals tested, with no modulation of NMDA glutamate receptors. Moreover, the generation of APs, as opposed to the average level of somatic depolarization during priming, was necessary for triggering the metaplasticity. Our results provide solid evidence for a pro‐homeostatic metaplasticity that is engaged by postsynaptic AP firing, thus impeding the saturation of Hebbian plasticity and associated hyperexcitability.
Parkinson's disease (PD) encompasses motor and neuropsychiatric symptoms (NPS) including depression, anxiety, and apathy. Cognitive subtypes-PD with mild cognitive impairment (PD-MCI) and PD with dementia (PDD)-and the related Dementia with Lewy Bodies (DLB) exist within the spectrum of Lewy body disease (LBD). While NPS are a major comorbidity, established imaging biomarkers are not available, nor is the neuronal basis well known. Additionally, prevalence of NPS may be linked to cognitive status. The hippocampus is implicated in the development of NPS and may undergo microstructural changes that are not reflected in volume changes. High-resolution diffusion tensor imaging (DTI) was used to identify hippocampal changes in LBD compared to healthy controls (HC) and examine the relationship with NPS within the LBD group, both through association with DTI measures as well as comparison of cognitive subgroups. The hippocampus was manually segmented in 38 LB spectrum participants (aged 58-87 years, 32% female) and 35 HC (aged 50-83 years, 54% female) on high-resolution (1 × 1 × 1 mm3) DTI. The LBD group (LBD-All) was divided into LBD-Cognitively Impaired (LBD-CI) and LBD-Cognitively Unimpaired (LBD-CU). Hippocampal volume, mean diffusivity (MD), and fractional anisotropy (FA) were extracted and compared across groups. Relationships between significantly different hippocampal measures and depression, anxiety, and apathy were explored within the LBD-All group. Hippocampal FA was lower in LBD-All relative to HC; however, no differences in MD or volume were observed. Hippocampal FA was positively associated with depression scores within LBD-All. There were no differences in volume, MD, or FA between LBD-CI and LBD-CU. Lower hippocampal fractional anisotropy in the LBD spectrum relative to HC potentially reflects microstructure alterations; however, higher hippocampal FA in LBD with more severe depression suggests more complex microstructural changes such as altered synaptic density, Lewy neurite organization, or neuroplastic changes.
The study of cross-species differences in the organization of the cerebral cortex received significant attention during the past century. However, the evolutionary principles governing changes in brain connectivity and their impact on cognition remain poorly understood. In the current study, we analyzed differences in anatomical input from the cerebral cortex to the hippocampal region across six species spanning more than 100 million years of mammalian evolution-the tenrec, rat, cat, marmoset, macaque and human. Our results demonstrate that, unlike direct transmodal cortical input, direct unimodal cortical input to the hippocampal region was selectively eliminated with the increase in brain size. Additionally, input from primary sensory regions was eliminated prior to input from non-primary sensory regions. Our findings suggest that hippocampus-related processes in different species operate on fundamentally different types of information, potentially underpinning cross-species differences in hippocampus-dependent cognition. Furthermore, our findings outline the evolutionary trajectory of the anatomical circuitry associating the human hippocampal region with the neocortex.
