Comparison of head direction cell firing characteristics across thalamo-parahippocampal circuitry.

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.

A thalamo-parietal cortex circuit is critical for place-action coordination.

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.

Sexually dimorphic organization of open field behavior following moderate prenatal alcohol exposure.

BACKGROUND: Prenatal alcohol exposure (PAE) can produce deficits in a wide range of cognitive functions but is especially detrimental to behaviors requiring accurate spatial information processing. In open field environments, spatial behavior is organized such that animals establish "home bases" marked by long stops focused around one location. Progressions away from the home base are circuitous and slow, while progressions directed toward the home base are non-circuitous and fast. The impact of PAE on the organization of open field behavior has not been experimentally investigated. METHODS: In the present study, adult female and male rats with moderate PAE or saccharin exposure locomoted a circular high walled open field for 30 minutes under lighted conditions. RESULTS: The findings indicate that PAE and sex influence the organization of open field behavior. Consistent with previous literature, PAE rats exhibited greater locomotion in the open field. Novel findings from the current study indicate that PAE and sex also impact open field measures specific to spatial orientation. While all rats established a home base on the periphery of the open field, PAE rats, particularly males, exhibited significantly less clustered home base stopping with smaller changes in heading between stops. PAE also impaired progression measures specific to distance estimation, while sex alone impacted progression measures specific to direction estimation. CONCLUSIONS: These findings support the conclusion that adult male rats have an increased susceptibility to the effects of PAE on the organization of open field behavior.

Immediate-early gene Homer1a intranuclear transcription focus intensity as a measure of relative neural activation.

Immediate-early genes (IEGs) exhibit a rapid, transient transcription response to neuronal activation. Fluorescently labeled mRNA transcripts appear as bright intranuclear transcription foci (INF), which have been used as an all-or-nothing indicator of recent neuronal activity; however, it would be useful to know whether INF fluorescence can be used effectively to assess relative activations within a neural population. We quantified the Homer1a (H1a) response of hippocampal neurons to systematically varied numbers of exposures to the same places by inducing male Long-Evans rats to run laps around a track. Previous studies reveal relatively stable firing rates across laps on a familiar track. A strong linear trend (r2 > 0.9) in INF intensity was observed between 1 and 25 laps, after which INF intensity declined as a consequence of dispersion related to the greater elapsed time. When the integrated fluorescence of the entire nucleus was considered instead, the linear relationship extended to 50 laps. However, there was only an approximate doubling of H1a detected for this 50-fold variation in total spiking. Thus, the intranuclear H1a RNA fluorescent signal does provide a relative measure of how many times a set of neurons was activated over a ~10 min period, but the dynamic range and hence signal-to-noise ratios are poor. This low dynamic range may reflect previously reported reductions in the IEG response during repeated episodes of behavior over longer time scales. It remains to be determined how well the H1a signal reflects relative firing rates within a population of neurons in response to a single, discrete behavioral event.

Do the anterior and lateral thalamic nuclei make distinct contributions to spatial representation and memory?

The anterior and lateral thalamus has long been considered to play an important role in spatial and mnemonic cognitive functions; however, it remains unclear whether each region makes a unique contribution to spatial information processing. We begin by reviewing evidence from anatomical studies and electrophysiological recordings which suggest that at least one of the functions of the anterior thalamus is to guide spatial orientation in relation to a global or distal spatial framework, while the lateral thalamus serves to guide behavior in relation to a local or proximal framework. We conclude by reviewing experimental work using targeted manipulations (lesion or neuronal silencing) of thalamic nuclei during spatial behavior and single-unit recordings from neuronal representations of space. Our summary of this literature suggests that although the evidence strongly supports a working model of spatial information processing involving the anterior thalamus, research regarding the role of the lateral thalamus is limited and requires further attention. We therefore identify a number of major gaps in this research and suggest avenues of future study that could potentially solidify our understanding of the relative roles of anterior and lateral thalamic regions in spatial representation and memory.

Interaction of egocentric and world-centered reference frames in the rat posterior parietal cortex.

Navigation requires coordination of egocentric and allocentric spatial reference frames and may involve vectorial computations relative to landmarks. Creation of a representation of target heading relative to landmarks could be accomplished from neurons that encode the conjunction of egocentric landmark bearings with allocentric head direction. Landmark vector representations could then be created by combining these cells with distance encoding cells. Landmark vector cells have been identified in rodent hippocampus. Given remembered vectors at goal locations, it would be possible to use such cells to compute trajectories to hidden goals. To look for the first stage in this process, we assessed parietal cortical neural activity as a function of egocentric cue light location and allocentric head direction in rats running a random sequence to light locations around a circular platform. We identified cells that exhibit the predicted egocentric-by-allocentric conjunctive characteristics and anticipate orienting toward the goal.

The Prominence of Action Sequences and Behavioral Similarity in the Morris Water Task.

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. Supplementary Information: The online version contains supplementary material available at 10.1007/s40614-024-00402-8.

Organization of spontaneous spatial behaviors under dark conditions is unaffected in adult male and female long-Evans rats after moderate prenatal alcohol exposure.

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. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Anxiety and Alzheimer's disease pathogenesis: focus on 5-HT and CRF systems in 3xTg-AD and TgF344-AD animal models.

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.

Selective In Vitro and Ex Vivo Staining of Brain Neurofibrillary Tangles and Amyloid Plaques by Novel Ethylene Ethynylene-Based Optical Sensors.

The identification of protein aggregates as biomarkers for neurodegeneration is an area of interest for disease diagnosis and treatment development. In this work, we present novel super luminescent conjugated polyelectrolyte molecules as ex vivo sensors for tau-paired helical filaments (PHFs) and amyloid-ß (Aß) plaques. We evaluated the use of two oligo-p-phenylene ethynylenes (OPEs), anionic OPE12- and cationic OPE24+, as stains for fibrillar protein pathology in brain sections of transgenic mouse (rTg4510) and rat (TgF344-AD) models of Alzheimer's disease (AD) tauopathy, and post-mortem brain sections from human frontotemporal dementia (FTD). OPE12- displayed selectivity for PHFs in fluorimetry assays and strong staining of neurofibrillary tangles (NFTs) in mouse and human brain tissue sections, while OPE24+ stained both NFTs and Aß plaques. Both OPEs stained the brain sections with limited background or non-specific staining. This novel family of sensors outperformed the gold-standard dye Thioflavin T in sensing capacities and co-stained with conventional phosphorylated tau (AT180) and Aß (4G8) antibodies. As the OPEs readily bind protein amyloids in vitro and ex vivo, they are selective and rapid tools for identifying proteopathic inclusions relevant to AD. Such OPEs can be useful in understanding pathogenesis and in creating in vivo diagnostically relevant detection tools for neurodegenerative diseases.

An Integrated Platform for In Vivo Electrophysiology in Spatial Cognition Experiments.

Spatial 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.

Head direction cell activity in the anterodorsal thalamus requires intact supragenual nuclei.

Neural activity in several limbic areas varies as a function of the animal's head direction (HD) in the horizontal plane. Lesions of the vestibular periphery abolish this HD cell signal, suggesting an essential role for vestibular afference in HD signal generation. The organization of brain stem pathways conveying vestibular information to the HD circuit is poorly understood; however, recent anatomical work has identified the supragenual nucleus (SGN) as a putative relay. To test this hypothesis, we made lesions of the SGN in rats and screened for HD cells in the anterodorsal thalamus. In animals with complete bilateral lesions, the overall number of HD cells was significantly reduced relative to control animals. In animals with unilateral lesions of the SGN, directional activity was present, but the preferred firing directions of these cells were unstable and less influenced by the rotation of an environmental landmark. In addition, we found that preferred directions displayed large directional shifts when animals foraged for food in a darkened environment and when they were navigating from a familiar environment to a novel one, suggesting that the SGN plays a critical role in projecting essential self-motion (idiothetic) information to the HD cell circuit.

Control of anterodorsal thalamic head direction cells by environmental boundaries: comparison with conflicting distal landmarks.

Experiments were conducted to determine whether environmental boundaries exert preferential control over the tuning of head direction (HD) cells. In each experiment, HD cells were recorded in the rat anterodorsal thalamus while they foraged for randomly scattered food in trapezoid- and rectangle-shaped environments. After an initial recording session, each environment was rotated 90°, and changes in the preferred firing directions of HD cells were monitored. Rats were disoriented before each test session to prevent the use of self-movement cues to maintain orientation from one session to the next. In Experiment 1, we demonstrate that HD cell tuning consistently shifted in register with the trapezoid shaped enclosure, but was more variable in the rectangle shaped environment. In Experiments 2 and 3, we show that the strong control by the trapezoid persists in the presence of one clearly visible distal landmark, but not when three or more distal landmarks, including view of the recording room, are present. Together, the results indicate that distinct environmental boundaries exert strong stimulus control over HD cell orientation. However, this geometric control can be overridden with a sufficient number of salient distal landmarks. These results stand in contrast to the view that information from geometric cues usually takes precedence over information from landmark cues.

Differential effects of chronic stress on anxiety-like behavior and contextual fear conditioning in the TgF344-AD rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that leads to severe cognitive and functional impairments. Many AD patients also exhibit neuropsychiatric symptoms, such as anxiety and depression, prior to the clinical diagnosis of dementia. Chronic stress is associated with numerous adverse health consequences and disease states, and AD patients exhibit altered stress systems. Thus, stress may represent a causal link between neuropsychiatric symptoms and AD. To address this possibility, we examined the effects of chronic stress in the TgF344-AD rat model that co-expresses the mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1ΔE9) genes. Adult male transgenic (Tg+) and wild-type (WT) rats (6-7.5 months of age), with and without a history of chronic restraint stress, were tested for footshock-induced conditioned fear and for anxiety-like behavior in the elevated plus-maze. We found that non-stressed Tg+ rats showed increased anxiety-like behavior compared to non-stressed WT rats. In contrast, Tg+ and WT rats did not differ in levels of freezing immediately following footshock or during contextual re-exposure. Additionally, stressed Tg+ rats were not significantly different from stressed WT rats on any measures of anxiety or fear. Thus, while stress has been linked as a risk factor for AD-related pathology, it appears from the present findings that two weeks of daily restraint stress did not further enhance anxiety- or fear-like behaviors in TgF344-AD rats.

Impaired head direction cell representation in the anterodorsal thalamus after lesions of the retrosplenial cortex.

The retrosplenial cortex (RSP), a brain region frequently linked to processes of spatial navigation, contains neurons that discharge as a function of a rat's head direction (HD). HD cells have been identified throughout the limbic system including the anterodorsal thalamus (ADN) and postsubiculum (PoS), both of which are reciprocally connected to the RSP. The functional relationship between HD cells in the RSP and those found in other limbic regions is presently unknown, but given the intimate connectivity between the RSP and regions such as the ADN and PoS, and the reported loss of spatial orientation in rodents and humans with RSP damage, it is likely that the RSP plays an important role in processing the limbic HD signal. To test this hypothesis, we produced neurotoxic or electrolytic lesions of the RSP and recorded HD cells in the ADN of female Long-Evans rats. HD cells remained present in the ADN after RSP lesions, but the stability of their preferred firing directions was significantly reduced even in the presence of a salient visual landmark. Subsequent tests revealed that lesions of the RSP moderately impaired landmark control over the cells' preferred firing directions, but spared the cells directional stability when animals were required to update their orientation using self-movement cues. Together, these results suggest that the RSP plays a prominent role in processing landmark information for accurate HD cell orientation and may explain the poor directional sense in humans that follows damage to the RSP.

Both visual and idiothetic cues contribute to head direction cell stability during navigation along complex routes.

Successful navigation requires a constantly updated neural representation of directional heading, which is conveyed by head direction (HD) cells. The HD signal is predominantly controlled by visual landmarks, but when familiar landmarks are unavailable, self-motion cues are able to control the HD signal via path integration. Previous studies of the relationship between HD cell activity and path integration have been limited to two or more arenas located in the same room, a drawback for interpretation because the same visual cues may have been perceptible across arenas. To address this issue, we tested the relationship between HD cell activity and path integration by recording HD cells while rats navigated within a 14-unit T-maze and in a multiroom maze that consisted of unique arenas that were located in different rooms but connected by a passageway. In the 14-unit T-maze, the HD signal remained relatively stable between the start and goal boxes, with the preferred firing directions usually shifting <45° during maze traversal. In the multiroom maze in light, the preferred firing directions also remained relatively constant between rooms, but with greater variability than in the 14-unit maze. In darkness, HD cell preferred firing directions showed marginally more variability between rooms than in the lighted condition. Overall, the results indicate that self-motion cues are capable of maintaining the HD cell signal in the absence of familiar visual cues, although there are limits to its accuracy. In addition, visual information, even when unfamiliar, can increase the precision of directional perception.

Intact landmark control and angular path integration by head direction cells in the anterodorsal thalamus after lesions of the medial entorhinal cortex.

The medial entorhinal cortex (MEC) occupies a central position within neural circuits devoted to the representation of spatial location and orientation. The MEC contains cells that fire as a function of the animal's head direction (HD), as well as grid cells that fire in multiple locations in an environment, forming a repeating hexagonal pattern. The MEC receives inputs from widespread areas of the cortical mantle including the ventral visual stream, which processes object recognition information, as well as information about visual landmarks. The role of the MEC in processing the HD signal or landmark information is unclear. We addressed this issue by neurotoxically damaging the MEC and recording HD cells within the anterodorsal thalamus (ADN). Direction-specific activity was present in the ADN of all animals with MEC lesions. Moreover, the discharge characteristics of ADN HD cells were only mildly affected by MEC lesions, with HD cells exhibiting greater anticipation of future HDs. Tests of landmark control revealed that HD cells in lesioned rats were capable of accurately updating their preferred firing directions in relation to a salient visual cue. Furthermore, cells from lesioned animals maintained stable preferred firing directions when locomoting in darkness and demonstrated stable HD cell tuning when locomoting into a novel enclosure, suggesting that MEC lesions did not disrupt the integration of idiothetic cues, or angular path integration, by HD cells. Collectively, these findings suggest that the MEC plays a limited role in the formation and spatial updating of the HD cell signal.

Anxiety and Alzheimer's disease: Behavioral analysis and neural basis in rodent models of Alzheimer's-related neuropathology.

Alzheimer's disease (AD) pathology is commonly associated with cognitive decline but is also composed of neuropsychiatric symptoms including psychological distress and alterations in mood, including anxiety and depression. Emotional dysfunction in AD is frequently modeled using tests of anxiety-like behavior in transgenic rodents. These tests often include the elevated plus-maze, light/dark test and open field test. In this review, we describe prototypical behavioral paradigms used to examine emotional dysfunction in transgenic models of AD, specifically anxiety-like behavior. Next, we summarize the results of studies examining anxiety-like behavior in transgenic rodents, noting that the behavioral outcomes using these paradigms have produced inconsistent results. We suggest that future research will benefit from using a battery of tests to examine emotional behavior in transgenic AD models. We conclude by discussing putative, overlapping neurobiological mechanisms underlying AD-related neuropathology, stress and anxiety-like behavior reported in AD models.

Head direction cell instability in the anterior dorsal thalamus after lesions of the interpeduncular nucleus.

Previous research has identified a population of cells throughout the limbic system that discharge as a function of the animal's head direction (HD). Altering normal motor cues can alter the HD cell responses and disrupt the updating of their preferred firing directions, thus suggesting that motor cues contribute to processing the HD signal. A pathway that conveys motor information may stem from the interpeduncular nucleus (IPN), a brain region that has reciprocal connections with HD cell circuitry. To test this hypothesis, we produced electrolytic or neurotoxic lesions of the IPN and recorded HD cells in the anterior dorsal thalamus (ADN) of rats. Direction-specific firing remained present in the ADN after lesions of the IPN, but measures of HD cell properties showed that cells had reduced peak firing rates, large directional firing ranges, and firing that predicted the animal's future heading more than in intact controls. Furthermore, preferred firing directions were moderately less influenced by rotation of a salient visual landmark. Finally, the preferred directions of cells in lesioned rats exhibited large shifts when the animals foraged for scattered food pellets in a darkened environment and when locomoting from a familiar environment to a novel one. We propose that the IPN contributes motor information about the animal's movements to the HD cell circuitry. Furthermore, these results suggest that the IPN plays a broad role in the discharge properties and stability of direction-specific activity in the HD cell circuit.

Directional learning, but no spatial mapping by rats performing a navigational task in an inverted orientation.

Previous studies have identified neurons throughout the rat limbic system that fire as a function of the animal's head direction (HD). This HD signal is particularly robust when rats locomote in the horizontal and vertical planes, but is severely attenuated when locomoting upside-down (Calton & Taube, 2005). Given the hypothesis that the HD signal represents an animal's sense of directional heading, we evaluated whether rats could accurately navigate in an inverted (upside-down) orientation. The task required the animals to find an escape hole while locomoting inverted on a circular platform suspended from the ceiling. In Experiment 1, Long-Evans rats were trained to navigate to the escape hole by locomoting from either one or four start points. Interestingly, no animals from the 4-start point group reached criterion, even after 29 days of training. Animals in the 1-start point group reached criterion after about six training sessions. In Experiment 2, probe tests revealed that animals navigating from either 1- or 2-start points utilized distal visual landmarks for accurate orientation. However, subsequent probe tests revealed that their performance was markedly attenuated when navigating to the escape hole from a novel start point. This absence of flexibility while navigating upside-down was confirmed in Experiment 3 where we show that the rats do not learn to reach a place, but instead learn separate trajectories to the target hole(s). Based on these results we argue that inverted navigation primarily involves a simple directional strategy based on visual landmarks.