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Scholarly Works (15 results)

  • Thesis
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UC Irvine Electronic Theses and Dissertations (2021)

ABSTRACT OF THE DISSERTATIONNicotine Effect on Auditory Processing: an Unexpected Role of the alpha-2 Nicotinic Acetylcholine Receptor by Susan Gil Doctor of Philosophy in Biological Sciences University of California, Irvine, 2021 Dr. Raju Metherate, Chair Nicotine enhances cortical neurophysiology and higher cognitive functions, such as attention, learning and memory. This enhancement is presumably mediated by activation of nicotinic acetylcholine receptors (nAChRs), located within central cholinergic systems that mediate attention and other higher brain functions. Subsequently, nAChR agonists are being considered as prospective therapeutics for treating cognitive disorders. However, the nAChR family is comprised of many subtypes, which differ in composition, expression density, distribution, and nicotinic action. A prudent approach to better inform drug development is to investigate the unique contribution(s) of individual nAChR subtypes to nicotinic cognitive enhancement. Moreover, it is important to consider the possible involvement of less common (and underexamined) nAChR subunits and the role they may play in the overall outcomes of nAChR activation. Using the mouse auditory system, the following experiments explore the physiological role and laminar expression of the alpha2 nicotinic acetylcholine receptor (a2nAChR). xiii In Chapter 1, I used in-vivo electrophysiology within mouse primary auditory cortex (A1), to investigate the role of the underexamined a2nAChR in nicotinic effects on auditory processing. Current-source density recordings within A1 of anesthetized mice revealed that activation of a2nAChRs is involved in the nicotinic enhancement of responses to pure tone stimuli. In fact, compared to wild-type (WT) mice, nicotinic enhancement of A1 responses is altered in mice where the a2 gene has been deleted (a2KO). In Chapter 2, in order to survey respective laminar distributions, and co-expression within the auditory cortex (ACx), I used immunolabeling of parvalbumin (PV), vasoactive intestinal peptide (VIP), and somatostatin (SOM) interneuron markers on brain sections of mice expressing the enhanced green-fluorescent reporter protein (eGFP). Driven by the a2 promoter, eGFP fluoresced in cells containing the a2nAChR subunit (resulting mice are referred to as a2eGFP mice). We found that a2nAChRs were almost exclusively expressed in Layer V, and generally localized with SOM-expressing interneurons. Together these chapters represent the initial physiological and anatomical investigations of a2nAChRs in the ACx. They serve to further our understanding of a2nAChRs function in auditory processing.

    Cover page: Nicotinic Effect on Auditory Processing: an Unexpected Role of the alpha2 Nicotinic Acetylcholine Receptor
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2021)
    Systemic nicotine enhances neural processing in primary auditory cortex (A1) as determined using tone-evoked, current-source density (CSD) measurements. For example, nicotine enhances the characteristic frequency (CF)-evoked current sink in layer 4 of A1, increasing amplitude and decreasing latency. However, since presenting auditory stimuli within a stream of stimuli increases the complexity of response dynamics, we sought to determine the effects of nicotine on CSD responses to trains of CF stimuli (one-second trains at 2-40 Hz; each train repeated 25 times). CSD recordings were obtained using a 16-channel multiprobe inserted in A1 of urethane/xylazine-anesthetized mice, and analysis focused on two current sinks in the middle (layer 4) and deep (layers 5/6) layers. CF trains produced adaptation of the layer 4 response that was weak at 2 Hz, stronger at 5-10 Hz and complete at 20-40 Hz. In contrast, the layer 5/6 current sink exhibited less adaptation at 2-10 Hz, and simultaneously recorded auditory brainstem responses (ABRs) showed no adaptation even at 40 Hz. Systemic nicotine (2.1 mg/kg) enhanced layer 4 responses throughout the one-second stimulus train at rates ≤10 Hz. Nicotine enhanced both response amplitude within each train and the consistency of response timing across 25 trials. Nicotine did not alter the degree of adaptation over one-second trials, but its effect to increase amplitudes revealed a novel, slower form of adaptation that developed over multiple trials. Nicotine did not affect responses that were fully adapted (20-40 Hz trains), nor did nicotine affect any aspect of the layer 5/6 current sink or ABRs. The overall effect of nicotine in layer 4 was to enhance all responses within each train, to emphasize earlier trials across multiple trials, and to improve the consistency of timing across all trials. These effects may improve processing of complex acoustic streams, including speech, that contain information in the 2-10 Hz range.
      Cover page: Nicotine Enhances Amplitude and Consistency of Timing of Responses to Acoustic Trains in A1
      • Thesis
      • Peer Reviewed
      UC Irvine Electronic Theses and Dissertations (2018)

      Nicotinic acetylcholine receptor (nAChR) activation has been shown to improve sensory-cognitive function. In the auditory system, nicotine (an agonist of nAChRs) enhances the brain’s response to attended, relevant stimuli while reducing the response to distracters. Activation of nAChRs has a similar ability to improve stimulus detection in other sensory systems and while it is a remarkable and consistent finding, there is a lack of comprehensive studies on the neural activity behind this phenomenon. Using the mouse auditory system as a model, here we test the role of nAChRs in auditory processing, specifically spectral processing, and the underlying cortical circuitry driving nicotine’s effects.

      In Chapter 1, we used a tone-in-notched-noise stimulus to examine how nicotine influences the ability to filter incoming frequency information. Current-source density recordings in the primary auditory cortex of the anesthetized mouse revealed that systemic nicotine effectively narrows receptive fields, increases response gain in the center of the receptive field, and enhances responses to the tone. Subsequent manipulations demonstrated that modulation of cortical receptive fields and tone-evoked responses occurred at multiple levels in the ascending auditory pathway. These actions at nAChRs in cortical and subcortical circuits, which mimic effects of auditory attention, likely contribute to the nicotinic enhancement of sensory and cognitive processing.

      In Chapter 2, we performed whole-cell recordings in the auditory cortex of mouse brain slices to investigate the role of discrete cell types. Bath application of nicotine selectively depolarized pyramidal (Pyr) and vasoactive intestinal peptide (VIP)- containing neurons and enhanced spontaneous inhibitory post-synaptic currents (sIPSC) in Pyr, VIP, and SOM cells. We found that VIP cell activation is responsible for both the nicotinic depolarization and sIPSC enhancement observed in Pyr neurons, implicating a disinhibitory neural circuit in the nicotinic modulation of cortex. This disinhibition likely renders Pyr cells more excitable and responsive to incoming stimuli, thus providing a probable mechanism for nicotine’s beneficial effects on cortical processing and function.

      Together with the findings in Chapter 1, these results further reveal the neural basis of nicotine’s effects and substantiate efforts to use nicotine as a therapeutic for those with cognitive or sensory processing disorders.

        Cover page: Nicotine's effects on auditory processing and the role of cortical interneurons
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2016)
        This Special Issue focuses on the auditory-evoked mismatch negativity (MMN), an electrophysiological index of change, and its reduction in schizophrenia. The following brief review is an attempt to complement the behavioral and clinical contributions to the Special Issue by providing basic information on synaptic interactions and processing in auditory cortex. A key observation in previous studies is that the MMN involves activation of cortical N-methyl-D-aspartate (NMDA) receptors. Yet, NMDA receptor activation is regulated by a number of synaptic events, which also may contribute to the MMN reduction in schizophrenia. Accordingly, this review will focus on synaptic interactions, notably inhibitory regulation of NMDA receptor-mediated activity, in auditory cortex.
          Cover page: Synaptic interactions and inhibitory regulation in auditory cortex
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2019)
          Activation of nicotinic acetylcholine receptors (nAChRs) enhances sensory-cognitive function in human subjects and animal models, yet the neural mechanisms are not fully understood. This review summarizes recent studies on nicotinic regulation of neural processing in the cerebral cortex that point to potential mechanisms underlying enhanced cognitive function. Studies from our laboratory focus on nicotinic regulation of auditory cortex and implications for auditory-cognitive processing, but relevant emerging insights from multiple brain regions are discussed. Although the major contributions of the predominant nAChRs containing α7 (homomeric receptors) or α4 and β2 (heteromeric) subunits are well recognized, recent results point to additional, potentially critical contributions from α2 subunits that are relatively sparse in cortex. Ongoing studies aim to elucidate the specific contributions to cognitive and cortical function of diverse nAChRs. IMPLICATIONS:This review highlights the therapeutic potential of activating nAChRs in the cerebral cortex to enhance cognitive function. Future work also must determine the contributions of relatively rare but important nAChR subtypes, potentially to develop more selective treatments for cognitive deficits.
            Cover page: Enhanced Sensory–Cognitive Processing by Activation of Nicotinic Acetylcholine Receptors
            • Article
            • Peer Reviewed
            UC Irvine Previously Published Works (2017)
            Nicotine enhances sensory and cognitive processing via actions at nicotinic acetylcholine receptors (nAChRs), yet the precise circuit- and systems-level mechanisms remain unclear. In sensory cortex, nicotinic modulation of receptive fields (RFs) provides a model to probe mechanisms by which nAChRs regulate cortical circuits. Here, we examine RF modulation in mouse primary auditory cortex (A1) using a novel electrophysiological approach: current-source density (CSD) analysis of responses to tone-in-notched-noise (TINN) acoustic stimuli. TINN stimuli consist of a tone at the characteristic frequency (CF) of the recording site embedded within a white noise stimulus filtered to create a spectral "notch" of variable width centered on CF. Systemic nicotine (2.1 mg/kg) enhanced responses to the CF tone and to narrow-notch stimuli, yet reduced the response to wider-notch stimuli, indicating increased response gain within a narrowed RF. Subsequent manipulations showed that modulation of cortical RFs by systemic nicotine reflected effects at several levels in the auditory pathway: nicotine suppressed responses in the auditory midbrain and thalamus, with suppression increasing with spectral distance from CF so that RFs became narrower, and facilitated responses in the thalamocortical pathway, while nicotinic actions within A1 further contributed to both suppression and facilitation. Thus, multiple effects of systemic nicotine integrate along the ascending auditory pathway. These actions at nAChRs in cortical and subcortical circuits, which mimic effects of auditory attention, likely contribute to nicotinic enhancement of sensory and cognitive processing.
              Cover page: Systemic Nicotine Increases Gain and Narrows Receptive Fields in A1 via Integrated Cortical and Subcortical Actions
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2011)
              Primary auditory cortex (A1) exhibits a tonotopic representation of characteristic frequency (CF). The receptive field properties of A1 neurons emerge from a combination of thalamic inputs and intracortical connections. However, the mechanisms that guide growth of these inputs during development and shape receptive field properties remain largely unknown. We previously showed that Eph family proteins help establish tonotopy in the auditory brainstem. Moreover, other studies have shown that these proteins shape topography in visual and somatosensory cortices. Here, we examined the contribution of Eph proteins to cortical organization of CF, response thresholds and sharpness of frequency tuning. We examined mice with null mutations in EphB2 and EphB3, as these mice show significant changes in auditory brainstem connectivity. We mapped A1 using local field potential recordings in adult EphB2−/ −;EphB3−/ − and EphB3−/ − mice, and in a central A1 location inserted a 16-channel probe to measure tone-evoked current-source density (CSD) profiles. Based on the shortest-latency current sink in the middle layers, which reflects putative thalamocortical input, we determined frequency receptive fields and sharpness of tuning (Q20) for each recording site. While both mutant mouse lines demonstrated increasing CF values from posterior to anterior A1 similar to wild type mice, we found that the double mutant mice had significantly lower Q20 values than either EphB3−/ − mice or wild type mice, indicating broader tuning. In addition, we found that the double mutants had significantly higher CF thresholds and longer onset latency at threshold than mice with wild type EphB2. These results demonstrate that EphB receptors influence auditory cortical responses, and suggest that EphB signaling has multiple functions in auditory system development.
                Cover page: Null Mutations in EphB Receptors Decrease Sharpness of Frequency Tuning in Primary Auditory CortexCreative Commons 'BY' version 4.0 license
                • Article
                • Peer Reviewed
                UC Irvine Previously Published Works (2012)
                  Cover page: Nicotinic filtering of sensory processing in auditory cortexCreative Commons 'BY' version 4.0 license
                  • Article
                  • Peer Reviewed
                  UC Irvine Previously Published Works (2019)
                  Nicotine activates nicotinic acetylcholine receptors and improves cognitive and sensory function, in part by its actions in cortical regions. Physiological studies show that nicotine amplifies stimulus-evoked responses in sensory cortex, potentially contributing to enhancement of sensory processing. However, the role of specific cell types and circuits in the nicotinic modulation of sensory cortex remains unclear. Here, we performed whole-cell recordings from pyramidal (Pyr) neurons and inhibitory interneurons expressing parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal peptide (VIP) in mouse auditory cortex, in vitro. Bath application of nicotine strongly depolarized and excited VIP neurons, weakly depolarized Pyr neurons, and had no effect on the membrane potential of SOM or PV neurons. The use of receptor antagonists showed that nicotine's effects on VIP and Pyr neurons were direct and indirect, respectively. Nicotine also enhanced the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in Pyr, VIP, and SOM, but not PV, cells. Using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), we show that chemogenetic inhibition of VIP neurons prevents nicotine's effects on Pyr neurons. Since VIP cells preferentially contact other inhibitory interneurons, we suggest that nicotine drives VIP cell firing to disinhibit Pyr cell somata, potentially making Pyr cells more responsive to auditory stimuli. In parallel, activation of VIP cells also directly inhibits Pyr neurons, likely altering integration of other synaptic inputs. These cellular and synaptic mechanisms likely contribute to nicotine's beneficial effects on cognitive and sensory function.
                    Cover page: Nicotine excites VIP interneurons to disinhibit pyramidal neurons in auditory cortex.
                    • Article
                    • Peer Reviewed
                    UC Irvine Previously Published Works (2016)
                    The GABAergic agonist muscimol is used to inactivate brain regions in order to reveal afferent inputs in isolation. However, muscimol's use in primary auditory cortex (A1) has been questioned on the grounds that it may unintentionally suppress thalamocortical inputs. We tested whether muscimol can preferentially suppress cortical, but not thalamocortical, circuits in urethane-anesthetized mice. We recorded tone-evoked current source density profiles to determine frequency receptive fields (RFs) for three current sinks: the "layer 4" sink (fastest onset, middle-layer sink) and current sinks 100 μm above ("layer 2/3") and 300 μm below ("layer 5/6") the main input. We first determined effects of muscimol dose (0.01-1 mM) on the characteristic frequency (CF) tone-evoked layer 4 sink. An "ideal" dose (100 μM) had no effect on CF-evoked sink onset latency or initial response but reduced peak amplitude by >80%, implying inhibition of intracortical, but not thalamocortical, activity. We extended the analysis to current sinks in layers 2/3 and 5/6 and for all three sinks determined RF breadth (quarter-octave steps, 20 dB above CF threshold). Muscimol reduced RF breadth 42% in layer 2/3 (from 2.4 ± 0.14 to 1.4 ± 0.11 octaves), 14% in layer 4 (2.2 ± 0.12 to 1.9 ± 0.10 octaves), and not at all in layer 5/6 (1.8 ± 0.10 to 1.7 ± 0.12 octaves). The results provide an estimate of the laminar and spectral extent of thalamocortical projections and support the hypothesis that intracortical pathways contribute to spectral integration in A1.
                      Cover page: Spectral breadth and laminar distribution of thalamocortical inputs to A1Creative Commons 'BY' version 4.0 license
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