Maternal behavior is the complex array of caregiving behaviors females display towards offspring. In rats, the transition to motherhood depends on the action of various hormones, especially estradiol near parturition, which primes the maternal circuitry to respond to pups upon first encounter at parturition with appropriate maternal behavior. Although virgin rats avoid pups, new mothers are highly motivated to interact with pups, and their maternal behavior depends on the functional interaction between the medial preoptic area (mPOA) and the ventral tegmental area (VTA). However, a precise mapping of the VTA-projecting mPOA neurons remains to be elucidated. To determine whether pup-responsive neurons in the mPOA project to the VTA, we injected the retrograde tracer Fluorogold (FG) into the VTA of new mother and virgin female rats. Six days later, females were exposed to 3 pups for 5 minutes, and their brains processed to visualize FG and c-Fos immunostaining. In addition, we further characterized the molecular phenotype of these neurons by performing immunohistochemistry against estrogen receptor alpha (Esr1). As expected, the behavior of postpartum and virgin females toward pups was different. Mothers readily approached pups and displayed maternal behavior, whereas virgins avoided interaction with pups. Despite these disparate responses to pups, no differences were found in the number and distribution of mPOAc-Fos→VTA neurons. In addition, in both postpartum and virgin females, a significant proportion of these pup-responsive mPOA→VTA projecting neurons also express Esr1. Further functional interrogation of these c-Fos+/Esr1+ mPOA→VTA neurons in virgins and mothers might elucidate distinct circuit dynamics potentially underlying their behavioral differences towards pups.

Olfactory sensory neurons (OSNs) are contained within the olfactory epithelium (OE) and are responsible for detecting odorant molecules in the air. The exposure of OSNs to the external environment is necessary for their function, but it also leaves them exposed to potentially harmful elements and thus results in a high turnover rate. Despite the high turnover, the olfactory sense is maintained throughout life through the division of a population of stem cells that produce new OSNs both during normal turnover and after an injury occurs in the OE. When new OSNs are born, they must extend axons from the OE to the olfactory bulb (OB) where they make specific synaptic contacts. To determine the timeline of axon extension in normal turnover and after a methimazole-induced injury, we used fate-tracing utilizing an inducible Cre-LoxP model in which a fluorescent reporter was expressed by neuronal precursors and subsequently used to track axonal growth as the OSNs matured. Our results show that axon extension in both conditions follow the same timeline. However, markers of synaptic connectivity in the OB were delayed after injury. The delay in synaptic connectivity was also corroborated with delays in olfactory behavior after injury, which took 40 days to recover to control levels. Additionally, we investigated the process of removal of axonal debris created after an injury. Immunohistochemical analysis after injury indicated upregulation of IBA1+ cells within the 3 olfactory nerve layer of the OB, suggesting a role of microglia in this process. These microglia also showed an activated morphology and some had very large cell bodies with multiple nuclei. Furthermore, qPCR analysis of post-injury OB tissue shows upregulation of the CD11b receptor that is expressed on microglia. Our results have also shown upregulation of components of the complement pathway after injury, which is suggestive of a mechanism that underlies axonal debris removal after injury in the OB. Taken together, these results shed light on the process by which the olfactory system is able to recover after injury and could lead to discovery of mechanisms that could translate to treatments for injuries in other areas of the nervous system.

Many complex actions are precomposed, by sequencing simpler motor actions. For such a complex action to be executed accurately, those simpler actions must be planned in the desired order, held in working memory, and then enacted one-by-one until the sequence is complete. Examples of this phenomenon include writing, typing, and speaking. Under most circumstances, the ability to learn and reproduce novel motor sequences is hindered when additional information is presented. However, in cases where the motor sequence is musical in nature (e.g. a choreographed dance or a piano melody), one must learn two sequences at the same time, one of motor actions and one of the time intervals between actions. Despite this added complexity, humans learn and perform rhythm-based motor sequences regularly. It has been shown that people can learn motoric and rhythmic sequences separately and then combine them with little trouble (Ullén & Bengtsson 2003). Also, functional MRI data suggest that there are distinct sets of neural regions responsible for the two different sequence types (Bengtsson et al. 2004). Although research on musical rhythm is extensive, few computational models exist to extend and inform our understanding of its neural bases. To that end, this dissertation introduces the TAMSIN (Timing And Motor System Integration Network) model, a systems-level neural network model designed to replicate rhythm-based motor sequence performance. TAMSIN utilizes separate Competitive Queuing (CQ) modules for motoric and temporal sequences, as well as modules designed to coordinate these sequence types into a cogent output performance consistent with a perceived beat and tempo. Chapters 1-4 explore prior literature on CQ architectures, rhythmic perception/production, and computational modeling, thereby illustrating the need for a model to tie those research areas together. Chapter 5 details the structure of the TAMSIN model and its mathematical specification. Chapter 6 presents and discusses the results of the model simulated under various circumstances. Chapter 7 compares the simulation results to behavioral and imaging results from the experimental literature. The final chapter discusses future modifications that could be made to TAMSIN to simulate aspects of rhythm learning, rhythm perception, and disordered productions, such as those seen in Parkinson’s disease.

The olfactory system is a great model for studying regeneration due to the olfactory epithelium’s regenerative capability which makes it a potential a source of neural stem cells. The olfactory epithelium presents three types of cells: sustentacular cells which provide support and act as glial supporting cells; olfactory sensory neurons that are in charge of detecting odorant molecules in the air; and the stem cells that generated the aforementioned cell types. Olfactory sensory neurons are constantly dying and being replaced by new neurons originating from the stem cells that lie at the base of the olfactory epithelium. We have used an injury model that allows us to remove all the olfactory sensory neurons from the olfactory epithelium, via a single injection of methimazole. Then, at different timepoints after injury we measure the functional recovery of the olfactory epithelium by analyzing the expression of specific synaptic associated markers. Specifically, we analyzed the expression of synaptophysin, tyrosine hydroxylase, vesicular glutamate transporter 1, and vesicular glutamate transporter 2. Simultaneously, we measured glomerular size in order to serve as an indicator of anatomical recovery. Finally, we correlate these findings with previously generated data in the lab associated with functional recovery through behavior.

The accessory olfactory bulb (AOB) processes pheromonal signals which in turn drive social behaviors. Here we identify a tract of aromatase-expressing (arom+) fibers in the dorsal lateral olfactory tract (dLOT) which terminate in the granule cell layer (GCL) of the AOB. We utilized a retrograde tracer in aromatase reporter animals to delineate the source of these fibers. We show that these input fibers emerge almost exclusively from a contiguous population of arom+ neurons that spans the bed nucleus of the accessory olfactory tract (BAOT) and posterioventral subnucleus of the medial amygdala (MeApv). This population of neurons expresses the estrogen receptor alpha and contains more aromatase neurons in male mice than female mice. Thus, this population of feedback neurons can detect neuroendocrine changes and modulate the output of AOB projection neurons in a way that is sexually dimorphic and could influence every downstream target of the AOB.

<p>This thesis aims to elucidate the mechanisms and response characteristics of neural circuits in the vertebrate brain capable of responding selectively to stimulus duration. The research within focused on, but is not limited to, auditory neurons; however, most of the results extend to other sensory modalities. These neurons are known, appropriately, as duration-tuned neurons (DTNs). Duration-tuned neurons tend to prefer stimulus durations similar to the duration of species-specific vocalizations and have preferred durations ranging from 1 ms up to over 100 ms across species.</p> <p>To study the mechanisms underlying DTNs, biologically inspired computational models were produced to explore previously hypothesized mechanisms of duration tuning. These models support the mechanisms by reproducing the responses of <em>in vivo</em> DTNs and predicting additional <em>in vivo</em> response characteristics. The models demonstrate an inherent flexibility in the mechanisms to extend across a wide range of durations and also reveal subtleties in response profiles that arise from particular model parameters.</p> <p>To quantify the encoding efficiency of <em>in vivo</em> DTNs, information theoretic measures were applied to the responses of 97 DTNs recorded from the auditory midbrain (inferior colliculus) of the big brown bat. Stimulus duration encoding robustness, as measured by stimulus-specific information, tended to align with the stimulus durations that produce the largest responses. In contrast, stimulus durations with the most sensitivity to changes in stimulus duration, as measured with an approximation of the observed Fisher information, tended to be stimulus durations shorter or longer than the duration evoking the largest response. Remarkably, both optimal and non-optional Bayesian decoding methods were able to accurately recover stimulus duration from population responses, including durations that lacked neurons dedicated to best representing that duration. These results suggest that DTNs are excellent at encoding stimulus duration, a feature that has been generally assumed but not previously quantified.</p> / Doctor of Philosophy (PhD)

<p>Tinnitus is an auditory disorder characterized by the perception of a ringing, hissing or buzzing sound with no external stimulus. Because the most common cause of chronic tinnitus is hearing loss, this neurological disorder is becoming increasingly prevalent in our noise-exposed and ageing society. With no cure and a lack of effective treatments, there is a need for a comprehensive understanding of the neural underpinnings of tinnitus. This dissertation outlines the development and validation of a comprehensive theoretical model of cortical correlates of tinnitus that is used to shed light on the development of tinnitus and to propose improvements to tinnitus treatment strategies.</p> <p>The first study involved the development of a computational model that predicts how homeostatic plasticity acting in the auditory cortex responds to hearing loss. A subsequent empirical study validated a more biologically plausible version of this computational model. The goal of these studies was to determine whether and how a form of plasticity that maintains balance in neural circuits can lead to aberrant activity in the auditory cortex. The final study extends the validated computational model to develop a comprehensive theoretical framework characterizing the potential role of homeostatic and Hebbian plasticity in the development of most major cortical correlates of tinnitus.</p> <p>These theoretical and empirical studies provide a novel and complete description of how neural plasticity in adult auditory cortex can respond to hearing loss and result in the development of tinnitus correlates.</p> / Doctor of Philosophy (PhD)

<p>The lateral superior olive (LSO) is an auditory brainstem nucleus crucial in the determination of sound source. To accomplish sound localization, principal neurons of the LSO compare the intensity of sounds reaching the two ears by integrating an excitatory input from the ipsilateral anteroventral cochlear nucleus (AVCN), which is activated by sound reaching one ear, with an inhibitory input from the ipsilateral medial nucleus of the trapezoid body (MNTB), which is activated by sound reaching the opposite ear. In order for LSO principal neurons to properly integrate these excitatory and inhibitory inputs, the inputs must be matched in a frequency-dependent matter to LSO neurons. The mechanisms that direct the organization, selection, and maturation of both the excitatory and inhibitory pathway during development are not well understood. The experiments presented in this thesis were aimed at understanding the mechanisms that may underlie these processes in the developing LSO.</p> <p>The excitatory neurotransmitter glutamate is released in both the excitatory AVCN-LSO pathway and the inhibitory MNTB-LSO pathway during their period of functional circuit refinement, and may be important in the development of both of these pathways. Using the patch-clamp technique in acute brainstem slices of rats, we evaluated glutamatergic transmission in both the excitatory AVCN-LSO pathway and the inhibitory MNTB-LSO pathway during their period of functional refinement. Additionally, using the patch-clamp technique in acute brainstem slices of mice, we examined what functions vesicular glutamate transporter 3 (VGlut3), the protein that supports glutamate release from MNTB terminals, may have in the developing MNTB-LSO pathway. When taken together, the results from the three studies presented support a model in which circuit maturation in the LSO relies on mechanisms driven through a specific glutamate receptor, the N-methyl-D-aspartate (NMDA) receptor.</p> / Doctor of Philosophy (PhD)

Attention uses sensory inputs and goals to select information from our environment. Monkey electrophysiological literature demonstrates that visuo-tactile bimodal neurons (respond to visual and tactile stimuli presented on/near the hand) facilitate multisensory integration. Human behavioral studies show that hand position/function bias visual attention. Event-related potentials (ERPs) reveal the cortical dynamics coordinating visual inputs, body position, and action goals. Early, sensory ERPs (N1) indicate multisensory integration. Later, cognitive ERPs (P3) reflect task-related processing. Study 1 investigates a discrepancy between monkey and human literatures. Monkey studies demonstrate bimodal neuron responses equidistantly around the whole hand, but human studies demonstrate attentional bias for grasping space. In a visual detection paradigm, participants positioned their hand so target and non-target stimuli appeared near the palm or back of the hand; ERPs were measured. N1 components indicated no amplitude differences between Palm vs. Back conditions, but P3 components revealed greater target vs. non-target differentiation for Palm conditions. Results suggest cortical timing underlies grasping vs. whole hand bias differences: early processing does not differentiate using hand function, but cognitive processing does when stimuli are discriminated for action. Study 2 investigates whether proprioceptive inputs facilitate visual processing. In a visual detection paradigm, participants viewed stimuli presented between occluders blocking view of a hand positioned either near or far from the stimuli. N1 amplitudes were similar for near and far conditions, but P3 amplitudes for target/non-target differences were accentuated for near conditions. Proprioceptive effects emerge later in processing. ERP reveals the cortical dynamics underlying hand position effects on vision.

HIV is capable of causing a set of neurological diseases collectively termed the HIV Associated Neurocognitive Disorders (HAND). Worsening pathology is observed in HIV+ individuals who use opioid drugs. Memory problems are often observed in HAND, implicating HIV pathology in the hippocampus, and are also known to be exacerbated by morphine use. HIV-1 Tat was demonstrated to reduce spatial memory performance in multiple tasks, and individual subsets of CA1 interneurons were found to be selectively vulnerable to the effects of Tat, notably nNOS+/NPY- interneurons of the pyramidal layer and stratum radiatum, PV+ neurons of the pyramidal layer, and SST+ neurons of stratum oriens. Each of these interneuron subsets are hypothesized to form part of a microcircuit involved in memory formation. Electrophysiological assessment of hippocampal pyramidal neurons with Tat and morphine together revealed that Tat caused a reduction in firing frequency, however, chronic morphine exposure did not have any effect. When morphine was removed after chronic exposure, non-interacting effects of Tat and morphine withholding on firing frequency were observed, suggesting that a homeostatic rebalancing of CA1 excitation/inhibition balance takes place in response to chronic morphine exposure independently of any Tat effects. Additionally, differential morphological effects of Tat and morphine were observed in each of the three major dendritic compartments, with SR being less affected, suggesting complex circuit responses to these insults reflecting local change and potentially changes in inputs from other brain regions. Behaviorally, Tat and morphine interactions occur in spatial memory, with morphine potentially obviating Tat effects.