Systems Neuroscience of Spatial Learning and Memory
Our laboratory makes use of several techniques to provide a systems-level investigation of the neural basis of spatial learning and memory. Specifically, we make use of techniques that allow monitoring of large numbers of neurons simultaneously (10s to 100s) while animals are engaged in specific spatial behaviors. To do this, trainees fabricate electrode arrays that can be adjusted to a specific anatomical targets. Neural signals are correlated with behavior in spatial navigation and learning and memory tasks. We make use of in vivo electrophysiology methods to investigate changes in neural circuits in pre-clinical models of developmental and neurodegenerative disorders. Using these in vivo electrophysiology techniques, our laboratory routinely records place cell, head direction cell, and grid cell activity as shown in the Figure below (from Harvey et al 2019).
Our laboratory has also conducted quantitative comparisons of neural decoding methods on head direction cell signals in thalamo-cortical circuitry. We specifically compared statistical model-based and machine learning approaches by assessing decoding accuracy and evaluated variables that contribute to population coding across thalamo-cortical head direction cells. Example tuning curves from head direction cells are shown below: the black curves are the true tuning functions, smoothed by a Gaussian kernel function, the red curves are the estimated functions using the Kalman Filter (KF) method, and the blue curves are the estimated functions using the Generalized Linear Model (GLM) method. The middle panel shows the true vs. decoded head angle from a population of simultaneously recorded head direction cells. The right panel shows the median absolute error for each brain region, each dataset, and each decoding method (from Xu et al 2019).
Spatial Learning and Memory and Fetal Alcohol Spectrum Disorders
A central focus of the Clark lab is the investigation of neurobiological changes corresponding to spatial learning and memory deficits in Fetal Alcohol Spectrum Disorders (reviewed in Harvey et al 2019). Specifically, our recent work (see Figure below) has shown that animals exposed to a moderate amount of alcohol prenatally can accurately perform sensory discriminations between complex objects, but are impaired when required to discriminate between objects on the basis of spatial location in the environment (Sanchez et al 2019). These observations suggest that the neural circuitry underlying object-place associations is impaired after developmental alcohol exposure and has motivated our subsequent studies on hippocampal function in Fetal Alcohol Spectrum Disorders.
Damage to the hippocampus is known to impair open field “exploratory” behavior (reviewed in Thompson et al 2018). Thus, we have recently studied the impact of prenatal alcohol exposure on open field locomotion in male and female adults (Osterlund Oltmanns et al 2022). In open field environments, locomotor behavior can be 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 (see left two panels of Figure below). Consistent with these previous studies, we showed that rats established a home base on the periphery of the open field. However, rats exposed to moderate alcohol prenatally, particularly male rats, exhibited significantly less clustered home base stopping (see right two panels in Figure below; from Osterlund Oltmanns et al 2022).
As described above, exposure to alcohol prenatally can result in deficits in spatial behavior but can also lead to a number of structural and synaptic alterations to hippocampal circuitry (e.g., Madden et al 2020). Consistent with this previous work, we recently found that hippocampal place cell activity is less spatially and directionally specific after moderate prenatal alcohol exposure (see Figure below; from Harvey et al 2020).
In healthy animals, spikes from place cells are systematically locked to theta cycles such that each spike shifts across successive cycles in a phenomenon known as theta phase precession (see left panel of Figure below). Consequently, the sequence of firing phases across a population of cells in a theta cycle corresponds to the sequence in which their respective spatial firing fields were traversed over several seconds. The compression of sequences from a behavioral timescale to the timescale at which neurons communicate may facilitate the strengthening of these sequences by spike-time dependent plasticity. In moderate PAE, we found that the proportion of place cells demonstrating theta phase precession was reduced in both environments (see right panel of Figure below; from Harvey et al 2020). This finding suggests that the sequential organization of place cell spiking is impaired after moderate PAE (see Wirt et al 2020 for discussion).
Behavior and in vivo electrophysiology studies point to a potential hippocampal circuit mechanism, and a potential systems-level basis, for spatial learning and memory deficits after developmental alcohol exposure. Our current research, which is supported by grants from the National Institutes on Alcohol Abuse and Alcoholism (R01 AA029700), is directed toward testing hypotheses regarding the role of hippocampal neural activity (and related neural circuits) in the encoding and “offline” consolidation of spatial learning and memory.
Funding for our research has been provided by the National Institutes on Alcohol Abuse and Alcoholism (R01 AA029700; R21 AA024983), the New Mexico Alcohol Research Center, the Alcohol Research Training in Neurosciences Program (T32 AA014127), the Alzheimer’s Association (AARG-17-531572), and University of New Mexico start-up funds.