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Open Access Publications from the University of California

Scholarly Works (7 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2023)

The hippocampus is critical for the acquisition and retrieval of episodic memory. Sensory information from cortical regions is conveyed to the hippocampus primarily via the lateral and medial perforant path (LPP, MPP) projections originating in the lateral and medial entorhinal cortex (LEC, MEC) respectively. The LPP projection has been shown to be involved in the transfer of information regarding cue identity, while the MPP conveys spatial information (Hargreaves et al., 2005; Reagh and Yassa, 2014). Within the hippocampus, the LPP sends its projections to both the dentate gyrus (DG) and field CA3 with evidence suggesting that these terminals can be extensions from the same axon (Yeckel and Berger, 1990; Tamamaki and Nojyo, 1993). However, comparisons between the two LPP branches, with regard to their release dynamics and synaptic plasticity mechanisms, are scarce and will thus be the focus of this dissertation. The manner in which the two LPP branches transform (i.e., amplify, filter) incoming signals to the hippocampus at behaviorally- relevant frequencies and patterns is relatively unknown. Multiple factors regulate frequency-dependent signal transformations (e.g. vesicle release dynamics) that can result in markedly different responses to similar inputs within the same network (Trieu et al., 2015). Chapter 1 characterizes the signal transformations at the LPP-DG branch located at the head-stage of the circuit. These studies demonstrate that the LPP-DG synapse operates as a low-pass filter, where responses to repetitive activation at ≥50 Hz (i.e., frequency) display within-train suppression. This operation appears to be governed by factors located in the presynaptic terminal associated with release probability and vesicle recycling. Indeed, the induction of a unique form of presynaptic long-term potentiation (LTP) at LPP-DG terminals increases the release probability and, as a result, enhances the low-pass filtering at this terminal. Given that the two LPP branches originate from the same axon, it would appear plausible that the unique release dynamics and LTP mechanisms evident at the LPP-DG terminal are also present at those synapses innervating CA3 pyramidal cells. However, as described in Chapter 2, recordings from the distal apical dendrites of field CA3 reveal that responses to repetitive stimulation are radically different than those seen in the DG. Within this node, 50 Hz frequency stimulation results in a frequency following as opposed to a depression, with lower frequencies acting similarly. These differences in frequency facilitation at the two LPP terminals suggest distinctions in vesicle release and recycling at the two sites. Furthermore, while LTP is expressed at presynaptic sites at the LPP-DG synapse, a postsynaptic variant of LTP that does not require endocannabinoid signaling is evident at LPP-CA3 terminals. These observations support a target-cell specification hypothesis for the production of LTP variants and suggest the preferential routing to, and encoding by, CA3. Finally, to emphasize the mechanistic differences in plasticity at these two terminals, a separate study, presented in Chapter 3 was conducted in which the effects that microglia had on LTP was assessed. Removal of microglia with the Colony Stimulating Factor-1 antagonist, PLX5622, had no effects on baseline synaptic responses at either LPP termination site (i.e., LPP-DG or LPP-CA3). However, when LTP was evaluated, mice that underwent PLX treatment had severe impairments at LPP-DG but not LPP-CA3 synapses. Although, the levels of the endocannabinoid, 2-AG, were elevated four-fold in the DG, the prevention of its breakdown fully restored LTP at these synapses. These results demonstrate that disruption of endocannabinoid signaling following microglia loss impairs LPP-DG LTP with no effect upon plasticity at LPP-CA3 terminals.

    Cover page: Factors Governing Information Transfer into the Primary Hippocampal Circuit
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2021)
    Evidence suggests encoding of recent episodic experiences may be enhanced by a subsequent salient event. We tested this hypothesis by giving rats a 3-min unsupervised experience with four odors and measuring retention after different delays. Animals recognized that a novel element had been introduced to the odor set at 24 but not 48 h. However, when odor sampling was followed within 5 min by salient light flashes or bedding odor, the memory lasted a full 2 d. These results describe a retroactive influence of salience to promote storage of episodic information and introduce a unique model for studying underlying plasticity mechanisms.
      Cover page: Retrograde enhancement of episodic learning by a postlearning stimulus
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2022)
      There is evidence that cannabis use during adolescence leads to memory and cognitive problems in young adulthood but little is known about effects of early life cannabis exposure on synaptic operations that are critical for encoding and organizing information. We report here that a 14-day course of daily Δ9-tetrahydrocannabinol treatments administered to adolescent rats and mice (aTHC) leads to profound but selective deficits in synaptic plasticity in two axonal systems in female, and to lesser extent male, hippocampus as assessed in adulthood. Adolescent-THC exposure did not alter basic synaptic transmission (input/output curves) and had only modest effects on frequency facilitation. Nevertheless, aTHC severely impaired the endocannabinoid-dependent long-term potentiation in the lateral perforant path in females of both species, and in male mice; this was reliably associated with impaired acquisition of a component of episodic memory that depends on lateral perforant path function. Potentiation in the Schaffer-commissural (S-C) projection to field CA1 was disrupted by aTHC treatment in females only and this was associated with both a deficit in estrogen effects on S-C synaptic responses and impairments to CA1-dependent spatial (object location) memory. In all the results demonstrate sexually dimorphic and projection system-specific effects of aTHC exposure that could underlie discrete effects of early life cannabinoid usage on adult cognitive function. Moreover they suggest that some of the enduring, sexually dimorphic effects of cannabis use reflect changes in synaptic estrogen action.
        Cover page: Persistent sexually dimorphic effects of adolescent THC exposure on hippocampal synaptic plasticity and episodic memory in rodents
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2018)

        Background

        Proper patterning of dendritic and axonal arbors is a critical step in the formation of functional neuronal circuits. Developing circuits rely on an array of molecular cues to shape arbor morphology, but the underlying mechanisms guiding the structural formation and interconnectivity of pre- and postsynaptic arbors in real time remain unclear. Here we explore how Down syndrome cell adhesion molecule (DSCAM) differentially shapes the dendritic morphology of central neurons and their presynaptic retinal ganglion cell (RGC) axons in the developing vertebrate visual system.

        Methods

        The cell-autonomous role of DSCAM, in tectal neurons and in RGCs, was examined using targeted single-cell knockdown and overexpression approaches in developing Xenopus laevis tadpoles. Axonal arbors of RGCs and dendritic arbors of tectal neurons were visualized using real-time in vivo confocal microscopy imaging over the course of 3 days.

        Results

        In the Xenopus visual system, DSCAM immunoreactivity is present in RGCs, cells in the optic tectum and the tectal neuropil at the time retinotectal synaptic connections are made. Downregulating DSCAM in tectal neurons significantly increased dendritic growth and branching rates while inducing dendrites to take on tortuous paths. Overexpression of DSCAM, in contrast, reduced dendritic branching and growth rate. Functional deficits mediated by tectal DSCAM knockdown were examined using visually guided behavioral assays in swimming tadpoles, revealing irregular behavioral responses to visual stimulus. Functional deficits in visual behavior also corresponded with changes in VGLUT/VGAT expression, markers of excitatory and inhibitory transmission, in the tectum. Conversely, single-cell DSCAM knockdown in the retina revealed that RGC axon arborization at the target is influenced by DSCAM, where axons grew at a slower rate and remained relatively simple. In the retina, dendritic arbors of RGCs were not affected by the reduction of DSCAM expression.

        Conclusions

        Together, our observations implicate DSCAM in the control of both pre- and postsynaptic structural and functional connectivity in the developing retinotectal circuit, where it primarily acts as a neuronal brake to limit and guide postsynaptic dendrite growth of tectal neurons while it also facilitates arborization of presynaptic RGC axons cell autonomously.
          Cover page: DSCAM differentially modulates pre- and postsynaptic structural and functional central connectivity during visual system wiringCreative Commons 'BY' version 4.0 license
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2022)
          Despite its evident importance to learning theory and models, the manner in which the lateral perforant path (LPP) transforms signals from entorhinal cortex to hippocampus is not well understood. The present studies measured synaptic responses in the dentate gyrus (DG) of adult mouse hippocampal slices during different patterns of LPP stimulation. Theta (5 Hz) stimulation produced a modest within-train facilitation that was markedly enhanced at the level of DG output. Gamma (50 Hz) activation resulted in a singular pattern with initial synaptic facilitation being followed by a progressively greater depression. DG output was absent after only two pulses. Reducing release probability with low extracellular calcium instated frequency facilitation to gamma stimulation while long-term potentiation, which increases release by LPP terminals, enhanced within-train depression. Relatedly, per terminal concentrations of VGLUT2, a vesicular glutamate transporter associated with high release probability, were much greater in the LPP than in CA3-CA1 connections. Attempts to circumvent the potent gamma filter using a series of short (three-pulse) 50 Hz trains spaced by 200 ms were only partially successful: composite responses were substantially reduced after the first burst, an effect opposite to that recorded in field CA1. The interaction between bursts was surprisingly persistent (>1.0 s). Low calcium improved throughput during theta/gamma activation but buffering of postsynaptic calcium did not. In all, presynaptic specializations relating to release probability produce an unusual but potent type of frequency filtering in the LPP. Patterned burst input engages a different type of filter with substrates that are also likely to be located presynaptically. KEY POINTS: The lateral perforant path (LPP)-dentate gyrus (DG) synapse operates as a low-pass filter, where responses to a train of 50 Hz, γ frequency activation are greatly suppressed. Activation with brief bursts of γ frequency information engages a secondary filter that persists for prolonged periods (lasting seconds). Both forms of LPP frequency filtering are influenced by presynaptic, as opposed to postsynaptic, processes; this contrasts with other hippocampal synapses. LPP frequency filtering is modified by the unique presynaptic long-term potentiation at this synapse. Computational simulations indicate that presynaptic factors associated with release probability and vesicle recycling may underlie the potent LPP-DG frequency filtering.
            Cover page: Novel types of frequency filtering in the lateral perforant path projections to dentate gyrus
            • Article
            • Peer Reviewed
            UC Irvine Previously Published Works (2021)
            Why layers II/III of entorhinal cortex (EC) deteriorate in advance of other regions during the earliest stages of Alzheimer's disease is poorly understood. Failure of retrograde trophic support from synapses to cell bodies is a common cause of neuronal atrophy, and we accordingly tested for early-life deterioration in projections of rodent layer II EC neurons. Using electrophysiology and quantitative imaging, changes in EC terminals during young adulthood were evaluated in male rats and mice. Field excitatory postsynaptic potentials, input/output curves, and frequency following capacity by lateral perforant path (LPP) projections from lateral EC to dentate gyrus were unchanged from 3 to 8-10 months of age. In contrast, the unusual presynaptic form of long-term potentiation (LTP) expressed by the LPP was profoundly impaired by 8 months in rats and mice. This impairment was accompanied by a reduction in the spine to terminal endocannabinoid signaling needed for LPP-LTP induction and was offset by an agent that enhances signaling. There was a pronounced age-related increase in synaptophysin within LPP terminals, an effect suggestive of incipient pathology. Relatedly, presynaptic levels of TrkB-receptors mediating retrograde trophic signaling-were reduced in the LPP terminal field. LTP and TrkB content were also reduced in the medial perforant path of 8- to 10-month-old rats. As predicted, performance on an LPP-dependent episodic memory task declined by late adulthood. We propose that memory-related synaptic plasticity in EC projections is unusually sensitive to aging, which predisposes EC neurons to pathogenesis later in life.SIGNIFICANCE STATEMENT Neurons within human superficial entorhinal cortex are particularly vulnerable to effects of aging and Alzheimer's disease, although why this is the case is not understood. Here we report that perforant path projections from layer II entorhinal cortex to the dentate gyrus exhibit rapid aging in rodents, including reduced synaptic plasticity and abnormal protein content by 8-10 months of age. Moreover, there was a substantial decline in the performance of an episodic memory task that depends on entorhinal cortical projections at the same ages. Overall, the results suggest that the loss of plasticity and related trophic signaling predispose the entorhinal neurons to functional decline in relatively young adulthood.
              Cover page: Rapid Aging in the Perforant Path Projections to the Rodent Dentate Gyrus
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2019)
              Ventral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors in male rats, querying the roles of DA neuron inhibitory and excitatory G-protein signaling in these processes. Designer receptor stimulation of Gq signaling, but not Gs signaling, in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory Gi/o signaling in DA neurons blunted the reinforcing and priming effects of cocaine, reduced stress-potentiated reinstatement, and altered behavioral strategies for cocaine seeking and taking. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein-signaling cascades, and DA neuron efferent targets, highlighting their multifaceted roles in addiction.SIGNIFICANCE STATEMENT G-protein-coupled receptors are crucial modulators of ventral tegmental area (VTA) dopamine neuron activity, but how this metabotropic signaling impacts the complex roles of dopamine in reward and addiction is poorly understood. Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs (designer receptors exclusively activated by designer drugs) during a variety of cocaine-seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. Gq and Gs stimulation activated dopamine neurons, but only Gq stimulation robustly enhanced cocaine seeking. Gi/o inhibitory signaling reduced some, but not all, types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction- and relapse-related behaviors, and point to potential new approaches for intervening in these processes to treat addiction.
                Cover page: Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse
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