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Open Access Publications from the University of California

Scholarly Works (5 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2022)

The serotonin system, among other neurotransmitter systems, plays an important role in mood and anxiety disorders. Stress, which is the biggest risk factor for the development of mood and anxiety disorders, leads to many lifelong changes that affect the overall function of monoamine transmission and behavior. My dissertation work set out to investigate (1) the effects of in utero stress exposure on neurochemistry and behavior during adulthood and whether concomitant maternal citalopram treatment rescued adverse stress effects, (2) the selectivity of optogenetically stimulating dopamine neurons and the interplay between monoamine systems, (3) SERT genotypes on freezing behaviors after ambiguous cue presentation, and (4) neuroinflammation produced by biosensors to monitor neurotransmitters in vivo. The primary investigation of my graduate work was focused on effects of in utero stress exposure and whether treatment with citalopram could mitigate the adverse effects of stress. To investigate this question, I used a mouse model in which pregnant dams underwent a chronic stress paradigm during their pregnancy. Some dams received concomitant treatment with citalopram, an SSRI. I then examined developmental neurochemistry, and adult neurochemical and behavioral changes. I found that pups from the stressed group had elevated neurochemical and amino acid tissue levels. Moreover, I found that pups born to stressed dams had increases in anxiety- and depressive- like behavior and that these effects were rescued in pups that received concomitant in utero citalopram exposure. Finally, stressed pups had increased serotonin concentrations after SERT blockade in the vHPC and after a systemic injection of a kappa opioid receptor agonist. My findings suggest beneficial outcomes when treating stress during pregnancy on overall offspring health.

    Cover page: Investigating Changes in Monoamine Transmission Induced by Stress
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2022)
      Cover page: Opioid Systems and Depression: The Relationship Is Strengthening
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2022)
      Targeting neurons with light-driven opsins is widely used to investigate cell-specific responses. We transfected midbrain dopamine neurons with the excitatory opsin Chrimson. Extracellular basal and stimulated neurotransmitter levels in the dorsal striatum were measured by microdialysis in awake mice. Optical activation of dopamine cell bodies evoked terminal dopamine release in the striatum. Multiplexed analysis of dialysate samples revealed that the evoked dopamine was accompanied by temporally coupled increases in striatal 3-methoxytyramine, an extracellular dopamine metabolite, and in serotonin. We investigated a mechanism for dopamine-serotonin interactions involving striatal dopamine receptors. However, the evoked serotonin associated with optical stimulation of dopamine neurons was not abolished by striatal D1- or D2-like receptor inhibition. Although the mechanisms underlying the coupling of striatal dopamine and serotonin remain unclear, these findings illustrate advantages of multiplexed measurements for uncovering functional interactions between neurotransmitter systems. Furthermore, they suggest that the output of optogenetic manipulations may extend beyond opsin-expressing neuronal populations.
        Cover page: Optogenetic Stimulation of Midbrain Dopamine Neurons Produces Striatal Serotonin Release.
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2021)
        Many voltammetry methods have been developed to monitor brain extracellular dopamine levels. Fewer approaches have been successful in detecting serotonin in vivo. No voltammetric techniques are currently available to monitor both neurotransmitters simultaneously across timescales, even though they play integrated roles in modulating behavior. We provide proof-of-concept for rapid pulse voltammetry coupled with partial least squares regression (RPV-PLSR), an approach adapted from multi-electrode systems (i.e., electronic tongues) used to identify multiple components in complex environments. We exploited small differences in analyte redox profiles to select pulse steps for RPV waveforms. Using an intentionally designed pulse strategy combined with custom instrumentation and analysis software, we monitored basal and stimulated levels of dopamine and serotonin. In addition to faradaic currents, capacitive currents were important factors in analyte identification arguing against background subtraction. Compared to fast-scan cyclic voltammetry-principal components regression (FSCV-PCR), RPV-PLSR better differentiated and quantified basal and stimulated dopamine and serotonin associated with striatal recording electrode position, optical stimulation frequency, and serotonin reuptake inhibition. The RPV-PLSR approach can be generalized to other electrochemically active neurotransmitters and provides a feedback pipeline for future optimization of multi-analyte, fit-for-purpose waveforms and machine learning approaches to data analysis.
          Cover page: Simultaneous serotonin and dopamine monitoring across timescales by rapid pulse voltammetry with partial least squares regression.
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2024)
          The Center for Disease Control and Prevention estimates that 75% of reported cases of traumatic brain injury (TBI) are mild, where chronic pain and depression are 2 of the most common symptoms. In this study, we used a murine model of repeated mild TBI to characterize the associated pain hypersensitivity and affective-like behavior and to what extent microglial reactivity contributes to these behavioral phenotypes. Male and female C57BL/6J mice underwent sham or repeated mild traumatic brain injury (rmTBI) and were tested for up to 9 weeks postinjury, where an anti-inflammatory/neuroprotective drug (minocycline) was introduced at 5 weeks postinjury in the drinking water. Repeated mild traumatic brain injury mice developed cold nociceptive hypersensitivity and negative affective states, as well as increased locomotor activity and risk-taking behavior. Minocycline reversed negative affect and pain hypersensitivities in male but not female mice. Repeated mild traumatic brain injury also produced an increase in microglial and brain-derived neurotropic factor mRNA transcripts in limbic structures known to be involved in nociception and affect, but many of these changes were sex dependent. Finally, we show that the antiepileptic drug, gabapentin, produced negative reinforcement in male rmTBI mice that was prevented by minocycline treatment, whereas rmTBI female mice showed a place aversion to gabapentin. Collectively, pain hypersensitivity, increased tonic-aversive pain components, and negative affective states were evident in both male and female rmTBI mice, but suppression of microglial reactivity was only sufficient to reverse behavioral changes in male mice. Neuroinflammation in limbic structures seems to be a contributing factor in behavioral changes resulting from rmTBI.
            Cover page: Neuroinflammation drives sex-dependent effects on pain and negative affect in a murine model of repeated mild traumatic brain injury.
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