Pathophysiological Study of Dopamine in Alzheimer's Disease and Related Demantia

National Institute On Aging

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Abstract

PD-related dementia (PDD) affects a significant portion of PD patients, ranging from 50-80%. Notably, the Ventral Tegmental Area Dopamine-Containing Neurons (VTA DANs) also degenerate in PD patients, which is thought to contribute to non-motor symptoms. Among the VTA DANs, a major subpopulation known as ALDH1A1/VGLUT2+ DANs forms direct synaptic connections with neurons in the lateral entorhinal cortex (LEC). The LEC plays a pivotal role in encoding multisensory information, encompassing tactile, olfactory, visual, and satiety-sensitive cues related to context. Additionally, LEC neurons are involved in representing temporal intervals concerning experiences, thereby assisting in the embedding of memory content within sequences or episodes. Recent findings have indicated that midbrain dopamine projection to the LEC is crucial for associative learning of rewarded cues, yet it remains unclear which specific population of midbrain DANs is essential for this function, and whether other LEC functions depend on midbrain DANs. We hypothesize that the degeneration of LEC-projecting VTA DANs contributes to cognitive impairments seen in PDD, particularly affecting episodic memory, by dysregulating LEC neuronal activity. To investigate the role of midbrain dopaminergic neuron (DAN) afferents in episodic memory formation, we employed inhibitory (Gi) or facilitatory (Gq) chemogenetic modulators, specifically DREADDs, in DATIRESCre-positive afferents to the LEC. Although we suspect low retrograde transfection efficiency using the CAV2 vectors in this study, we were still able to observe changes in tests designed to assess LEC function. During the learning phase of an episodic-like memory for novel object (ELMNO) paradigm, aimed at demonstrating recency and novelty discrimination, mice (including controls) did not successfully discriminate objects based on recency or novelty. However, both Gi and Gq mice exhibited increased exploration overall compared to controls, indicating a general memory impairment. We also evaluated temporal interval recall using a Peak Responding operant protocol, which revealed that impairing dopamine afferents to the LEC slowed the acquisition of a time-based task but did not critically affect task recall. Additionally, in the Trace Fear Conditioning test, Gq mice showed increased freezing, while Gi mice showed decreased freezing relative to controls, supporting a positive correlation between midbrain afferents to the LEC and the strength of associative learning. To further investigate modulatory factors and the timing of DAN afferent activity in the LEC, we plan to employ fiber photometry to record neuronal activity in these afferents during behavioral tasks. Building on our preliminary data, we will conduct modified versions of the ELMNO and Trace Fear tasks. Additionally, we will introduce a foraging-based episodic memory task on a Radial Arm Maze and a Serial Odor Discrimination task known to engage the LEC. The Peak Responding task will be replaced with a simplified cue-delay-reward Pavlovian task to assess temporal encoding. Moreover, we aim to differentiate the contributions of dopamine and glutamate from midbrain afferents. For this purpose, we have generated a cohort of dopamine D1-type receptor (Drd1) cKO mice, in which Drd1 is excised in the presence of Cre, and will locally inject Cre-carrying virus into the LEC before evaluating their episodic memory performance using the aforementioned behavioral tasks. Similarly, we will conduct analogous experiments in a cohort of glutamate transporter VGlut2 cKO mice to examine the effect of glutamate from VTA afferents to the LEC. Through these experiments, we aim to discern PDD-relevant behaviors that rely on midbrain afferents to the LEC, investigate the modulation of these afferents, and determine the critical involvement of dopamine and/or glutamate. As we move forward, we anticipate utilizing increasingly precise, genetically defined lesions and imaging techniques to pinpoint the specific midbrain DAN populations responsible for these effects.