Neuromodulatory subcortical systems (NSSs) are uniquely susceptible to dementia-related pathology, leading to frequent molecular and behavioral impairments associated with altered function of these nuclei. Some of these systems display clear sex-specific cytoarchitecture and signaling leading to distinct physiology and behavioral outputs in males and females, while other regions display nominal sex differences. However, the relevance of sex differences in modulating dysfunction of NSSs in Alzheimer's disease (AD) and related dementias is not well understood. This review is a joint effort by the Neuromodulatory Subcortical Systems and Sex and Gender Differences in Alzheimer's Disease Professional Interest Areas of the Alzheimer's Association. We review sex differences in NSSs, both in non-disease states and in AD models and patients. We highlight the possible role of NSSs in driving sex-specific AD susceptibility and potential footholds for sex-based interventions targeting these systems. We conclude by outlining immediate and long-term actions to address the intersection of NSSs, sex, and AD.

Background/Objectives: The growing aging population is susceptible to cognitive and memory impairment, most commonly due to Alzheimer’s disease, with no cures currently available. Noninvasive brain stimulation (NIBS) techniques may serve to improve cognition and delay catastrophic memory loss. Methods: A systematic review of NIBS research on cognitive impairment was carried out using PubMed, with additional backward citation searching. A total of 81 studies using NIBS were included. Conclusions: The reviewed studies show that NIBS holds promise in improving memory deficits in patients with cognitive impairment. While the longevity of benefits from transcranial electrical stimulation appears limited, its short-term effects may provide benefits when used consistently. Transcranial magnetic stimulation appears to provide longer-lasting benefits. Transcranial focused ultrasound stimulation may also provide further benefits through more precise targeting of deeper brain structures compared to other NIBS techniques. Together, these results suggest that NIBS shows promise for the treatment of symptoms related to cognitive and memory impairment, and may help to alleviate some of the growing issues associated with the increasing level of Alzheimer’s disease in an aging population.

Fetal Alcohol Spectrum Disorders (FASD) describe a range of neurobiological and behavioral changes following prenatal alcohol exposure. Previous work has shown that moderate prenatal alcohol exposure (mPAE) can produce alterations to GABAergic neurotransmission in the hippocampal formation (HPF) as well as morphological alterations in GABAergic interneuron expression in adult rats. In the present study, we tested the hypothesis that mPAE differentially alters GABAA subunit protein expression in dorsal and ventral HPF of naïve adult male and female Long-Evans control and mPAE rats. We focused our attention on the α1, α4, and α5 subunits as they have relatively high densities within the hippocampus and have been linked to hippocampal-dependent learning and memory. Membrane fractions were collected from dorsal and ventral HPF, and western blots were performed to detect levels of GABAA α1, α4, and α5 subunit protein expression. Overall, we did not detect prenatal treatment group differences suggesting that mPAE does not result in differential GABAA subunit protein expression in dorsal or ventral HPF of male and female rats. However, the results revealed significantly greater protein expression for α4 and α5 subunits in the dorsal HPF. GABAA α1 protein expression did not vary significantly across the dorsal and ventral HPF. Our findings support the general conclusion that GABAA subunit protein expression in the HPF reflects intrinsic regional specialization of GABAergic signaling rather than effects of mPAE.

Acute exposure to ethanol is known to produce significant alterations to the functions of the hippocampus leading to "blackouts" which are defined as temporary disruptions to the encoding and retention of memories. The hippocampus has a prominent role in generating representations of spatial location and contributes to spatial navigation. In open environments, spatial exploratory behaviors are organized such that animals spontaneously alternate between long duration stops (absence of movement) at a specific home base location and exploratory trips or progressions (locomotion between locations) into the remaining environment. Open field exploratory behaviors are organized even in darkness, suggesting a contribution of self-motion cues (e.g., vestibular) to spatial behavior. In the present study, we tested the hypothesis that acute single-dose ethanol exposure in adult mice would disrupt the expression of organized exploratory behaviors in an open field under darkened conditions. Male and female adult mice received a single injection of ethanol and explored a dark environment (under infrared light) for 30 min. Mice tested immediately after the injection exhibited reductions in locomotion and spontaneous behavior, while those tested 30 min later only exhibited suppressed locomotion. These results suggest that ethanol exposure leads to alterations in spontaneous exploratory behaviors.

Exposure to ethanol during gestation can lead to the onset of Fetal Alcohol Spectrum Disorders, which describes a range of neurodevelopmental and behavioral dysfunctions that include impairments in learning and memory and can have serious repercussions for scholastic performance during adolescence. The neurobiological basis of learning and memory dysfunction in Fetal Alcohol Spectrum Disorders has been frequently linked to the hippocampal formation, which is due in part to the fact that some hippocampal neurons, called place cells, fire action potentials correlated with an animal's spatial location as well as other features of memory episodes. The goal of this chapter is to provide an overview of research investigating developmental alcohol exposure in rodent models and the impact on learning and memory, hippocampal circuitry, and neural representations of learning and memory. We conclude by highlighting areas in which more concentrated behavioral and neurobiological study is needed to expand and develop rodent models of memory dysfunction in Fetal Alcohol Spectrum Disorders.

The neurobiological basis of spatial navigation has been the subject of intense debate in recent years. The neural systems thought to have a critical role in navigation include neurons located in the rodent hippocampus and in other limbic system structures that represent location and orientation. The purpose of this article is to critically evaluate the experimental work investigating the role of spatially responsive cells in the performance of navigation tasks and to highlight gaps in our understanding of this relationship.

Moderate prenatal alcohol exposure (mPAE) results in structural alterations to the hippocampus. Previous studies have reported impairments in hippocampal-sensitive tasks, but have not compared performance between male and female animals. In the present study, performance in hippocampal-sensitive spatial memory and anxiety behavior tests were compared across adult male and female saccharin (SACC) control mPAE Long-Evans rat offspring. Two tests of spatial memory were conducted that were aimed at assessing memory for recently acquired spatial information: A delayed spatial alternation task using an M-shaped maze and a delayed match-to-place task in the Morris water task. In both tasks, rats in SACC and mPAE groups showed similar learning and retention of a spatial location even after a 2-h interval between encoding and retention. A separate group of adult male and female SACC and mPAE rat offspring were tested for anxiety-like behaviors in the elevated plus-maze paradigm. In this test, both male and female mPAE rats exhibited a significantly greater amount of time and a greater number of head dips in the open arms, while locomotion and open arm entries did not differ between groups. The results suggest that mPAE produces a reduction in anxiety-like behaviors in both male and female rats in the elevated plus-maze.

The question of What is learned when navigating to a place is reinforced has been the subject of considerable debate. Prevailing views emphasize cognitive structures (e.g., maps) or associative learning, which has shaped measurement in spatial navigation tasks (e.g., the Morris water task [MWT]) toward selection of coarse measures that do not capture precise behaviors of individual animals. We analyzed the navigation paths of 15 rats (60 trials each) in the MWT at high temporal resolution (30Hz) and utilized dynamic time warping to quantify the similarity of paths within and between animals. Paths were largely direct, yet suboptimal, and included changes in speed and trajectory that were established early in training and unique to each animal. Individual rats executed similar paths from the same release point from trial to trial, which were distinct from paths executed by other rats as well as paths performed by the same rat from other release points. These observations suggest that rats learn to execute similar path sequences from trial to trial for each release point in the MWT. Occasional spontaneous deviations from the established, unique behavioral sequence, resulted in profound disruption in navigation accuracy. We discuss the potential implications of sequence navigation behaviors for understanding relations between behavior and spatial neural signals such as place cells, grid cells, and head direction cells.

Head direction (HD) cells, which fire persistently when an animal's head is pointed in a particular direction, are widely thought to underlie an animal's sense of spatial orientation and have been identified in several limbic brain regions. Robust HD cell firing is observed throughout the thalamo-parahippocampal system, although recent studies report that parahippocampal HD cells exhibit distinct firing properties, including conjunctive aspects with other spatial parameters, which suggest they play a specialized role in spatial processing. Few studies, however, have quantified these apparent differences. Here, we performed a comparative assessment of HD cell firing characteristics across the anterior dorsal thalamus (ADN), postsubiculum (PoS), parasubiculum (PaS), medial entorhinal (MEC), and postrhinal (POR) cortices. We report that HD cells with a high degree of directional specificity were observed in all five brain regions, but ADN HD cells display greater sharpness and stability in their preferred directions, and greater anticipation of future headings compared to parahippocampal regions. Additional analysis indicated that POR HD cells were more coarsely modulated by other spatial parameters compared to PoS, PaS, and MEC. Finally, our analyses indicated that the sharpness of HD tuning decreased as a function of laminar position and conjunctive coding within the PoS, PaS, and MEC, with cells in the superficial layers along with conjunctive firing properties showing less robust directional tuning. The results are discussed in relation to theories of functional organization of HD cell tuning in thalamo-parahippocampal circuitry.

Exposure to alcohol during pregnancy produces Fetal Alcohol Spectrum Disorders, which in its most severe form is characterized by physical dysmorphology and neurobehavioral alterations. Moderate prenatal alcohol exposure (mPAE) is known to produce deficits in discrimination of spatial locations in adulthood. However, the impact of mPAE on higher-order sensory representations, such as discrimination of perceptually similar stimuli, is currently unknown. In the present study, we tested the hypothesis that mPAE would disrupt performance on hippocampal-sensitive tasks that require discrimination between perceptually similar objects or discrimination between spatial locations in a radial arm maze. Here we report that male mPAE rats exhibited intact performance on three types of object discrimination tasks: one in which rats discriminated between distinct toy objects, a second in which discrimination was made between distinct and similar LEGO objects, and a mnemonic similarity task in which rats discriminated between randomly presented LEGO objects that varied in similarity with a learned object. Although adult male mPAE rats performed similarly to control rats on all three object discrimination tasks, they showed deficits when tested in a radial arm maze spatial discrimination task. Specifically, male mPAE rats expressed a significantly higher number of working memory errors (returns to previously visited arms) and were more likely to use non-spatial strategies during training. Together, the findings of the present study support the conclusion that mPAE produces specific deficits in the online processing of spatial information and executing spatial navigation strategies, but spares the ability to discriminate between perceptually similar stimuli.

Prenatal alcohol exposure can produce disruptions in a wide range of cognitive functions, but it is especially detrimental to spatial navigation. In open environments, rodents organize their spatial behaviors around centralized locations, termed home bases, from which they make circuitous and slow locomotor trips (progressions) into the rest of the environment. Open-field behaviors are organized even under darkened test conditions, suggesting a role for self-motion cues (vestibular, motor, etc.). The impact of moderate prenatal alcohol exposure (mPAE) on the organization of spontaneous open-field behaviors under darkened conditions has not been investigated. Here we tested adult female and male rats with mPAE or saccharin control exposure in a circular open field for 30 min in a testing room that was made completely dark. While general locomotion, as measured by reductions in travel distance and increased stop duration, decreased across the test session, the organization of these behaviors, as measured by stop duration, home base establishment, home base stability, progression accuracy, and scaling of peak speeds with progression length, did not differ between mPAE and saccharin control rats. Together, the findings strongly suggest that spontaneous movement organization in relation to self-motion cues remains intact in adult mPAE rats.

Autophagy is essential for cellular homeostasis and function. In neurons, autophagosome biogenesis is temporally and spatially regulated to occur near presynaptic sites, in part via the trafficking of autophagy transmembrane protein ATG-9. The molecules that regulate autophagy by sorting ATG-9 at synapses remain largely unknown. Here, we conduct forward genetic screens at single synapses of C. elegans neurons and identify a role for the long isoform of the active zone protein Clarinet (CLA-1L) in regulating sorting of autophagy protein ATG-9 at synapses, and presynaptic autophagy. We determine that disrupting CLA-1L results in abnormal accumulation of ATG-9 containing vesicles enriched with clathrin. The ATG-9 phenotype in cla-1(L) mutants is not observed for other synaptic vesicle proteins, suggesting distinct mechanisms that regulate sorting of ATG-9-containing vesicles and synaptic vesicles. Through genetic analyses, we uncover the adaptor protein complexes that genetically interact with CLA-1 in ATG-9 sorting. We also determine that CLA-1L extends from the active zone to the periactive zone and genetically interacts with periactive zone proteins in ATG-9 sorting. Our findings reveal novel roles for active zone proteins in the sorting of ATG-9 and in presynaptic autophagy.

The anterior and lateral thalamus (ALT) contains head direction cells that signal the directional orientation of an individual within the environment. ALT has direct and indirect connections with the parietal cortex (PC), an area hypothesized to play a role in coordinating viewer-dependent and viewer-independent spatial reference frames. This coordination between reference frames would allow an individual to translate movements toward a desired location from memory. Thus, ALT-PC functional connectivity would be critical for moving toward remembered allocentric locations. This hypothesis was tested in rats with a place-action task that requires associating an appropriate action (left or right turn) with a spatial location. There are four arms, each offset by 90°, positioned around a central starting point. A trial begins in the central starting point. After exiting a pseudorandomly selected arm, the rat had to displace the correct object covering one of two (left versus right) feeding stations to receive a reward. For a pair of arms facing opposite directions, the reward was located on the left, and for the other pair, the reward was located on the right. Thus, each reward location had a different combination of allocentric location and egocentric action. Removal of an object was scored as correct or incorrect. Trials in which the rat did not displace any objects were scored as "no selection" trials. After an object was removed, the rat returned to the center starting position and the maze was reset for the next trial. To investigate the role of the ALT-PC network, muscimol inactivation infusions targeted bilateral PC, bilateral ALT, or the ALT-PC network. Muscimol sessions were counterbalanced and compared to saline sessions within the same animal. All inactivations resulted in decreased accuracy, but only bilateral PC inactivations resulted in increased non selecting, increased errors, and longer latency responses on the remaining trials. Thus, the ALT-PC circuit is critical for linking an action with a spatial location for successful navigation.

Dementia remains one of the leading causes of morbidity and mortality in older adults. Alzheimer’s disease (AD) is the most common type of dementia, affecting over 55 million people worldwide. AD is characterized by distinct neurobiological changes, including amyloid-beta protein deposits and tau neurofibrillary tangles, which cause cognitive decline and subsequent behavioral changes, such as distress, insomnia, depression, and anxiety. Recent literature suggests a strong connection between stress systems and AD progression. This presents a promising direction for future AD research. In this review, two systems involved in regulating stress and AD pathogenesis will be highlighted: serotonin (5-HT) and corticotropin releasing factor (CRF). Throughout the review, we summarize critical findings in the field while discussing common limitations with two animal models (3xTg-AD and TgF344-AD), novel pharmacotherapies, and potential early-intervention treatment options. We conclude by highlighting promising future pharmacotherapies and translational animal models of AD and anxiety.

AbstractSpatial cognition research requires behavioral paradigms that can distinguish between different navigational elements, such as allocentric (map-like) navigation and egocentric (e.g., body centered) navigation. To fill this need, we developed a flexible experimental platform that can be quickly modified without the need for significant changes to software and hardware. In this paper, we present this inexpensive and flexible behavioral platform paired with software which we are making freely available. Our behavioral platform serves as the foundation for a range of experiments, and although developed for assessing spatial cognition, it also has applications in the nonspatial domain of behavioral testing. There are two components of the software platform, “Maze” and “Stim Trigger.” While intended as a general platform, presently both programs can work in conjunction with Neuralynx and Open Ephys electrophysiology acquisition systems, allowing for precise time stamping of neural events. The Maze program includes functionality for automatic reward delivery based on user defined zones. “Stim Trigger” permits control of brain stimulation via any equipment that can be paired with an Arduino board. We seek to share our software and leverage the potential by expanding functionality in the future to meet the needs of a larger community of researchers.