<p> At present, Alzheimer&rsquo;s disease (AD) is an incurable neurodegenerative dementia. It has been suggested that neuronal hyperexcitability contributes to AD, so we asked how hyperexcitability develops in a common mouse model of &beta;-amyloid neuropathology - Tg2576 mice. These mice overexpress the Swedish familial mutation of human-amyloid precursor protein (hAPP). Using video-EEG recordings, we found synchronized, large amplitude potentials resembling interictal spikes (IIS) in epilepsy at just 5 weeks of age, long before memory impairments or &beta;-amyloid deposition. Seizures were uncommon, but occurred later in life, suggesting that IIS are possibly the earliest form of hyperexcitability. Interestingly, IIS primarily occurred during rapid-eye movement (REM) sleep prior to the deposition of &beta;-amyloid. The interests are twofold. First, REM sleep is associated with increased cholinergic tone. Second, cholinergic impairments as well as degeneration are implicated in AD. Although previous studies suggest that cholinergic antagonists would worsen pathophysiology, the muscarinic antagonist atropine but not nicotinic antagonists reduced IIS frequency in animals prior to &beta;-amyloid deposition. In addition, we found a role for brain hyperexcitability during general anesthesia. Epileptiform discharges are both hyperexcitable and hypersynchronous across age in Tg2576 mice and wildtypes. Our findings identify that epileptiform discharges elicited during anesthesia mediates cognitive dysfunction and is exacerbated in A&beta; depositing brains. Taken together with results from prior studies, the data suggest that surprising and multiple mechanisms contribute to neural hyperexcitability. The data also suggest that IIS during sleep may be a biomarker for early detection of AD.</p><p>

Olfaction, the sense of smell, allows animals to perceive the multitude of volatile and nonvolatile molecules present in the environment. In many mammals, such as mice and rats, there are four unique chemosensory organs including the (1) main olfactory epithelium (MOE), (2) septal organ, (3) Grüneberg ganglion, and (4) vomeronasal organ (VNO). While the VNO detects some general volatile odorants, it is further specialized for the detection of behaviorally relevant nonvolatile odorants or pheromones. In rodents, the VNO is encased within a bony capsule and located at the base of the nasal cavity. Odorants are detected by vomeronasal sensory neuron (VSN)s, bipolar neurons with a single axon that projects to the accessory olfactory bulb of the brain and a single dendrite capped with microvilli that project into the lumen of the VNO. In the MOE, purinergic signaling through adenosine 5'-triphosphate (ATP) gated ionotropic P2X and G-protein coupled P2Y receptors contributes a neuroprotective and neuroregenerative pathway. As virtually nothing was known about purinergic signaling in the VNO, I set out to characterize the (1) presence of the purinergic receptors and (2) ATP release pathways. In isolated VSNs, ATP elicited an increase in intracellular calcium ([Ca2+]I) and an inward current with similar potency. Adenosine and the P2Y receptor agonists adenosine 5'-diphosphate (ADP), uridine 5'-triphosphate (UTP), and uridine 5'-diphosphate (UDP) were ineffective. The increase in [Ca2+]I was dependent upon extracellular calcium and the inward current elicited by ATP was partially blocked by the P2X receptor antagonists pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS) and 2',3'-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate (TNP-ATP). When coapplied with the natural stimulus dilute urine, ATP increased the inward current above that elicited by either dilute urine or ATP alone. Furthermore, ADP hyperpolarized the voltage dependence of steady state inactivation of voltage activated sodium current (INa) in a subset of VSNs. The hyperpolarization in the voltage dependence of steady state inactivation elicited by ADP was blocked in the presence of suramin, a purinergic receptor antagonist, but similar to that produced by 1-oleoyl-2-acetyl-sn-glycerol (OAG), a membrane permeable protein kinase C (PKC) activator. Neither ATP nor ADP affected the voltage dependence of activation, fast inactivation, or time dependent recovery from inactivation. Interestingly, ADP reversibly increased spike frequency but did not change an action potential's amplitude, latency, halfwidth, or threshold voltage. Accordingly, we detected gene expression of the P2X1 and 3 as well as P2Y1, 2, and 6 receptors in the VNO and localized the P2Y1 and 2 receptors to isolated VSNs. Thus, excitability in VSNs can be enhanced by (1) ATP eliciting an inward current through P2X receptors and (2) ADP decreasing spike adaptation during persistent firing presumably through P2Y receptors. Moreover, one possible source of ATP may be from mechanical stimulation of the VNO that accompanies vasomotor pump activation.

<p> Instinctive behaviors such as mating and aggression are key for the survival and propagation of species. As innate behaviors manifest without prior training, there must be embryonic genetic mechanisms that specify these innate behavioral circuits. Focusing on the MeA and hypothalamus, both major integration centers of olfactory inputs, first, we sought to elucidate the link between embryonic transcription factor expression, neuronal identity and innate behavioral activation patterns in the MeA, and second, the link between embryonic transcription factor expression and instinctive behavioral activation patterns in hypothalamic subnuclei. Using mice as a model organism, we observed that the MeA progenitor niche in the preoptic area (POA) is comprised of distinct progenitor populations differentially marked by the transcription factors Dbx1 and Foxp2. Both embryonically and postnatally, Dbx1-derived and Foxp2+ subpopulations remain spatially segregated. We also observed that Dbx1-derived and Foxp2+ neurons differentially express sets of sex-steroid pathway proteins. Furthermore, both subpopulations differed in their intrinsic and extrinsic electrophysiological properties. Additionally, behavioral activation patterns were investigated in both subpopulations by determining the co-expression of the immediate early gene c-fos, an indirect marker of neuronal activity. During aggressive encounters, both Dbx1-derived and Foxp2+ neurons were activated in male and female mice; however, during mating cues, Dbx1-derived neurons in male and female mice were activated while only Foxp2+ neurons in male mice were activated and not in female mice. This denotes sex-specific differences in behavioral activation patterns in the MeA. Thus, parcellation of MeA neuronal subpopulations based on developmental genetics predicts molecular, electrophysiological, and behavioral specificity. Secondly, we were interested in determining whether embryonic transcription factor expression would be predictive of innate behavioral activation patterns in other limbic system structures implicated in the generation of innate behaviors such as the hypothalamus. Interestingly, we observed the presence of Dbx1-derived neurons in the lateral (LH), arcuate (Arc) and ventromedial (VMH) hypothalamic subnuclei. As Foxp2+ neurons are not present in the hypothalamus, we only analyzed Dbx1-derived neurons in these three hypothalamic regions. We show that Dbx1-derived neurons are activated in these structures during mating and aggression in both male and female mice. Thus, embryonic transcription factor expression in the hypothalamus is also linked to postnatal behavioral activation patterns. Taken together our findings indicate that embryonic transcription factor expression is predictive of behavioral activation patterns in the limbic system. We found that progenitor populations present in the same region but expressing distinct transcription factors, can generate MeA postnatal diversity based on molecular, electrophysiological and behavioral activation patterns. Furthermore, this can be generalized to other limbic system structures such as the hypothalamus, in which embryonic transcription factor expression of Dbx1 is also predictive of activation patterns during instinctive behavioral cues.</p>

No description available.

<p>Perceiving or producing complex vocalizations such as speech and birdsongs require the coordinated activity of neuronal populations, and these activity patterns can vary over space and time. How learned communication signals are represented by populations of sensorimotor neurons essential to vocal perception and production remains poorly understood. Using a combination of two-photon calcium imaging, intracellular electrophysiological recording and retrograde tracing methods in anesthetized adult male zebra finches (<italic>Taeniopygia guttata</italic>), I addressed how the bird's own song and its component syllables are represented by the spatiotemporal patterns of activity of two spatially intermingled populations of projection neurons (PNs) in HVC, a sensorimotor area required for song perception and production. These experiments revealed that neighboring PNs can respond at markedly different times to song playback and that different syllables activate spatially intermingled HVC PNs within a small region. Moreover, noise correlation analysis reveals enhanced functional connectivity between PNs that respond most strongly to the same syllable and also provides evidence of a spatial gradient of functional connectivity specific to PNs that project to song motor nucleus (i.e. HVC_RA cells). These findings support a model in which syllabic and temporal features of song are represented by spatially intermingled PNs functionally organized into cell- and syllable-type networks.</p> / Dissertation

Pitch is an important attribute of auditory perception that conveys key features in music, speech, and helps listeners extract useful information from complex auditory environments. Although the psychophysics of pitch perception has been extensively studied for over a century, the underlying neural mechanisms are still poorly understood. This thesis examines pitch cues in the inferior colliculus (IC), which is the core processing center in the mammalian auditory midbrain that relays and transforms convergent inputs from peripheral brainstem nuclei to the auditory cortex. Previous studies have shown that IC can encode low-frequency fluctuations in stimulus envelope that are related to pitch, but most experiments were conducted in anesthetized animals using stimuli that only evoked weak pitch sensations and only investigated a limited frequency range. Here, we used single-neuron recordings from the IC in normal hearing, unanesthetized rabbits in response to a comprehensive set of complex auditory stimuli to explore the role of IC in the neural processing of pitch. We characterized three neural codes for pitch cues: a temporal code for the stimulus envelope repetition rate (ERR) below 900 Hz, a rate code for ERR between 60 and 1600 Hz, and a rate-place code for frequency components individually resolved by the cochlea that is mainly available above 800 Hz. While the temporal code and the rate-place code are inherited from the auditory periphery, the rate code for ERR has not been currently characterized in processing stages prior to the IC. To help interpret our experimental findings, we used computational models to show that the IC rate code for ERR likely arises via temporal interaction of multiple synaptic inputs, and thus the IC performs a temporal-to-rate code transformation from peripheral to cortical representations of pitch cues. We also show that the IC rate-place code is robust across a 40 dB range of sound levels, and is likely strengthened by inhibitory synaptic inputs. Together, these three codes could provide neural substrates for pitch of stimuli with various temporal and spectral compositions over the entire frequency range.

The cerebral cortex, the outer part of the brain that has expanded in humans, has layers whose differentiation varies within gradients. Along those gradients, we can define cortical types which range in number of layers and degrees of laminar differentiation. From least to most elaborate types there is an increase in the presence of granular layer IV, a shift in relative prominence of deep (layers V–VI) to superficial layers (layers II–III), and shift in location of large pyramidal neurons from deep (layers V–VI) to superficial layers (layers II–III), an increase in differentiation of deep layers (layers V–VI), and an increase in a defined boundary between layers I–II. According to this criteria, the following cortical types were defined: agranular, dysgranular, eulaminate I, and eulaminate II. In addition, primary areas in the cerebral cortex show distinct cortical features and are named koniocortices. Prior studies have shown that cortical types are related to epigenetics, synaptic plasticity, connections, pathologies, and evolution. Therefore, an algorithm to determine cortical type across areas in the human cortex will be a useful tool for the study of normal and pathological cortical networks. The Nissl stain, a standard histological staining method, was used in this study to observe differences in cortical type characteristics across the cerebral cortex. Qualitative analysis was performed on several cortical regions of an established neuroanatomical atlas, the prefrontal cortex of a post-mortem human, and the cerebral cortex of a rhesus macaque. Five laminar features were identified and used to group cortical regions into types, with less than 5% of disagreement amongst at least three experienced neuroanatomists. From these cortical type characteristics, an algorithm was created that can be used to systematically to determine cortical type throughout the cerebral cortex of humans and rhesus macaques. Additionally, quantitative analyses were performed in order to see if this cortical type classification could be an automated practice, that can be performed by individuals who are not experienced neuroanatomists. These quantitative measurements showed varying ability to classify cortical types; therefore, further studies will need to be performed in order to find the optimal quantitative measures of cortical type. A NMDS study was performed to summarize results of the various quantitative measurements, which showed an undisputable gradual trend of cortical types throughout the prefrontal cortex of the human brain. Overall, this study provides a cortical type classification algorithm that reliably and reproducibly identifies different cortical types in the cerebral cortex of human and rhesus macaque brains.

In this Dissertation, I report parallel processing in the avian vocal premotor nucleus HVC. First, I review historical ideas and recent evidence about the function of HVC. HVC has historically been viewed as a distributed network, and it has been modeled as an associative chain. Recent evidence shows that HVC intraconnectivity is biased along the rostral-caudal axis and that transecting HVC along the rostral-caudal axis does not disrupt singing. This evidence casts doubt on the historical views of HVC organization. Next, I explore the cytoarchitecture of HVC in order to determine whether distinct subregions within HVC exist. I then ablate these subregions to determine their functional significance. I find that the lateral portions of HVC encode the repertoire of song syllables, while the medial portions of HVC encode the sequence in which the syllables are sung. Finally, I utilize reversible inactivation of these subregions to confirm their functions. These results are the first evidence for parallel processing within the avian song control network and correspond with recent evidence for parallel processing in the neural control of human speech. / A Dissertation submitted to the Department of Psychology in partial fulfillment of the Doctor of Philosophy. / Spring Semester 2016. / April 11, 2016. / HVC, parallel processing, sequential behavior, zebra finch / Includes bibliographical references. / Frank Johnson, Professor Directing Dissertation; Walter Tschinkel, University Representative; Richard Bertram, Committee Member; Neil Charness, Committee Member; Richard Hyson, Committee Member; Wei Wu, Committee Member.

Traumatic Brain Injury (TBI) gives rise to a progressive disease state that results in many adverse and long-term neurological consequences, including deficits in learning and memory, development of major depressive disorder, and increased likelihood of developing neurodegenerative diseases, as well as decreased life expectancy. Mesenchymal stem cells (MSC) have emerged as a promising cytotherapy for TBI and have been previously shown to improve numerous cellular and behavioral outcomes after brain injury including reduction of secondary apoptosis, restriction of immune cell infiltration, and improvements in cognitive deficits such as spatial learning and memory. A number of molecules secreted by MSC have been implicated in their therapeutic mechanism of action. However, no studies have been conducted to examine the how the MSC secretome collectively regulates the injury microenvironment to support the survival of intact brain tissue that would otherwise be subject to secondary injury. The present study, uses high throughput RNA sequencing (RNAseq) of cortical tissue from the TBI penumbra to assess the molecular effects of both TBI and subsequent treatment with intravenously delivered human mesenchymal stem cells (hMSC). TBI was found to disrupt expression of approximately one quarter of the rat protein-encoding genome. Remarkably, hMSC treatment was found to normalize 49% of all transcripts regulated by TBI. This study also investigates the therapeutic efficacy of hMSC against negative behavioral outcomes commonly associated with TBI, including depression, which is the most common long-term side effect of TBI in humans. We show for the first time that a stem cell-based therapy is capable of preventing trauma-induced depression. Using novel precision X-ray methods to selectively eliminate endogenous neural stem cells, this study further probes the cellular mechanisms that underlie hMSC efficacy to reveal that some, but not all, therapeutic benefits conferred by hMSC treatment are dependent on active proliferation of endogenous neural progenitor cells in the subventricular zone. / A Dissertation submitted to the Department of Biomedical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Fall Semester 2015. / November 3, 2015. / Cytotherapy, Depression, Mesenchymal Stem Cells, Neural Progenitor Cells, Subventricular Zone, Traumatic Brain Injury / Includes bibliographical references. / Cathy W. Levenson, Professor Directing Dissertation; Geoffrey F. Strouse, University Representative; Samuel C. Grant, Committee Member; Timothy Megraw, Committee Member; Zuoxin Wang, Committee Member.

Sensory systems exploit parallel processing of stimulus features to enable rapid, simultaneous extraction of useful information. The mechanisms that facilitate differential extraction of stimulus features across neural pathways include intrinsic and synaptic features. A subdivision of the avian cochlear nucleus, Nucleus Angularis, extracts sound intensity information from the auditory nerve for sound localization, spectral processing, and identification purposes. Nucleus Angularis neurons consist of multiple cell subtypes, exhibit myriad responses to sound, and a wide span of efferent targets ascending the auditory brainstem. This work investigated whether auditory response patterns rely on intrinsic physiological features by coupling whole-cell recording in a brain slice with a computational model of acoustically-evoked auditory nerve input to Nucleus Angularis neurons via dynamic clamp. Results revealed that variation in intrinsic properties are sufficient to explain variation in auditory responses, and identified the low-threshold K+ current as a major contributor to temporal response diversity and neuronal input-output functions. Using the auditory nerve model to mimic acoustic amplitude modulation demonstrated that variation in intrinsic physiology was sufficient to generate temporal synchrony to modulation frequency, revealing variation in temporal modulation tuning across cell types. Variation in low-threshold K+ conductance was shown to alter temporal modulation tuning bidirectionally, with frequency-specific effects. Taken together, these data suggest that intrinsic physiological properties play a central role in shaping auditory response diversity to both simple and more naturalistic auditory stimuli. / A Dissertation submitted to the Department of Psychology in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Spring Semester 2018. / April 2, 2018. / auditory system, cochlear nucleus, computational modeling, electrophysiology, ion channel, sensory systems / Includes bibliographical references. / Richard L. Hyson, Professor Directing Dissertation; Geoffrey Strouse, University Representative; Frank Johnson, Committee Member; Michael Meredith, Committee Member; Christopher Patrick, Committee Member.