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Scholarly Works (7 results)

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UC Berkeley Electronic Theses and Dissertations (2018)

Abstract

The effects of early life adversity on the development of circuits

that support flexible decision-making

by

Alaina Wren Thomas

Doctor of Philosophy in Neuroscience

University of California, Berkeley

Professor Linda Wilbrecht, Chair

A large proportion of children in the United States experience childhood adversity, with over 50% reporting at least one adverse event. Early life adversity is strongly associated with increased risk for developing a number of physical and mental health disorders, yet the pathways linking childhood adversity to disease are not well understood.

This dissertation explores how the early environment can influence developing neural circuits, with a particular focus on neural circuits that support flexible goal-directed decision-making. Cognitive development plays a significant role in mental illness and prospects for recovery. Flexible decision-making is a major cognitive function that is impaired across multiple neuropsychiatric disorders including bipolar disorder and schizophrenia, that is also critical in supporting behavioral change.

In Chapter 2, I review my own collaborative work as well as work from others to describe the distinct developmental trajectories of sub-circuits that support flexible decision-making. I focus on frontal cortex dendritic spines and axonal boutons on afferents and efferents of the frontal cortex. These studies are motivated by the idea that identifying when these circuits grow and/or mature at the synaptic level will inform us when connections may be more vulnerable to adverse experiences and/or when interventions may have the greatest impact. I present in vivo imaging data that support previous classic findings that dendritic spines on frontal pyramidal neurons show loss of linear spine density, or in other words “prune,” across the adolescent period. However, I also present evidence that some long range frontal afferent and efferent circuits continue to grow and add synapses during the adolescent period, while others are pruning and stabilizing. These data refute the simple assumption that frontal circuits globally prune during adolescence, and raise questions about why some circuits show delayed growth.

Next, in Chapter 3, I explore how maternal separation, a mouse model of early life adversity, affects flexible decision-making across the lifespan. I find that this early life manipulation leads to changes in decision-making specifically at a juvenile, but not adult life stage. I hypothesize that changes in decision-making strategies at the juvenile time point, a point of first independence, may serve as a cognitive adaptation to signals that indicate a harsh environment.

Finally, in Chapter 4, I investigate how maternal separation and more specifically variations in maternal care, impact the development of four long range axons (two afferents and two efferents of the frontal cortex) that each play a role in flexible decision-making. I focus on changes at the adolescent life stage, based on differences in flexible decision-making at this age discussed in Chapter 3. I find that dorsomedial prefrontal cortex (dmPFC) axons that descend to target the basolateral amygdala (BLA) are specifically sensitive to the maternal separation manipulation and variations in maternal care, while the other three axons investigated show no relationship with early life care. Specifically, I found higher bouton density and smaller bouton size on dmPFC-BLA axons in maternally separated mice compared to controls. Additionally, bouton density on this projection correlated with maternal care measures, suggesting early maternal care (P1-10) may scale the later growth of this pathway (at P35). Variations in maternal care may serve as an indicator about the type of environment offspring are growing up in. These data support the idea that the brain can sample the statistics from the early environment and tune specific circuits to adapt to that environment.

Taken together, this thesis provides new insights about the development of circuits that support flexible decision-making. Importantly, I demonstrate how early life adversity impacts specific circuits at the synaptic level. These experiments provide high-resolution data that aims to help inform intervention and treatment strategies to promote healthy child development.

    Cover page: The effects of early life adversity on the development of circuits that support flexible decision-making
    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2016)
    Early life adversity is associated with increased risk for mental and physical health problems, including substance abuse. Changes in neural development caused by early life insults could cause or complicate these conditions. Maternal separation (MS) is a model of early adversity for rodents. Clear effects of MS have been shown on behavioral flexibility in rats, but studies of effects of MS on cognition in mice have been mixed. We hypothesized that previous studies focused on adult mice may have overlooked a developmental transition point when juvenile mice exhibit greater flexibility in reversal learning. Here, using a 4-choice reversal learning task we find that early MS leads to decreased flexibility in post-weaning juvenile mice, but no significant effects in adults. In a further study of voluntary ethanol consumption, we found that adult mice that had experienced MS showed greater cumulative 20% ethanol consumption in an intermittent access paradigm compared to controls. Our data confirm that the MS paradigm can reduce cognitive flexibility in mice and may enhance risk for substance abuse. We discuss possible interpretations of these data as stress-related impairment or adaptive earlier maturation in response to an adverse environment.
      Cover page: Early maternal separation impacts cognitive flexibility at the age of first independence in mice
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2020)
      Empirical and theoretical work suggests that early postnatal experience may inform later developing synaptic connectivity to adapt the brain to its environment. We hypothesized that early maternal experience may program the development of synaptic density on long range frontal cortex projections. To test this idea, we used maternal separation (MS) to generate environmental variability and examined how MS affected 1) maternal care and 2) synapse density on virally-labeled long range axons of offspring reared in MS or control conditions. We found that MS and variation in maternal care predicted bouton density on dorsal frontal cortex axons that terminated in the basolateral amygdala (BLA) and dorsomedial striatum (DMS) with more, fragmented care associated with higher density. The effects of maternal care on these distinct axonal projections of the frontal cortex were manifest at different ages. Maternal care measures were correlated with frontal cortex → BLA bouton density at mid-adolescence postnatal (P) day 35 and frontal cortex → DMS bouton density in adulthood (P85). Meanwhile, we found no evidence that MS or maternal care affected bouton density on ascending orbitofrontal cortex (OFC) or BLA axons that terminated in the dorsal frontal cortices. Our data show that variation in early experience can alter development in a circuit-specific and age-dependent manner that may be relevant to understanding the effects of early life adversity.
        Cover page: Variation in early life maternal care predicts later long range frontal cortex synapse development in mice
        • Article
        • Peer Reviewed
        UC Berkeley Previously Published Works (2018)
        Pyramidal neurons in the neocortex receive a majority of their synapses on dendritic spines, whose growth, gain, and loss regulate the strength and identity of neural connections. Juvenile brains typically show higher spine density and turnover compared to adult brains, potentially enabling greater capacity for experience-dependent circuit 'rewiring'. Although spine pruning and stabilization in frontal cortex overlap with pubertal milestones, it is unclear if gonadal hormones drive these processes. To address this question, we used hormone manipulations and in vivo 2-photon microscopy to test for a causal relationship between pubertal hormones and spine pruning and stabilization in layer 5 neurons in the frontal cortex of female mice. We found that spine density, gains, and losses decreased from P27 to P60 and that these measures were not affected by pre-pubertal hormone injections or ovariectomy. Further analyses of spine morphology after manipulation of gonadal hormones suggest that gonadal hormones may play a role in morphological maturation and dynamics. Our data help to segregate hormone-sensitive and hormone-insensitive maturational processes that occur simultaneously in dorsomedial frontal cortex. These data provide more specific insight into adolescent development and may have implications for understanding the neurodevelopmental effects of changes in pubertal timing in humans.
          Cover page: Adolescent pruning and stabilization of dendritic spines on cortical layer 5 pyramidal neurons do not depend on gonadal hormones
          • Article
          • Peer Reviewed
          UC Berkeley Previously Published Works (2016)
          The adolescent transition from juvenile to adult is marked by anatomical and functional remodeling of brain networks. Currently, the cellular and synaptic level changes underlying the adolescent transition are only coarsely understood. Here, we use two-photon imaging to make time-lapse observations of long-range axons that innervate the frontal cortex in the living brain. We labeled cells in the orbitofrontal cortex (OFC) and basolateral amygdala (BLA) and imaged their axonal afferents to the dorsomedial prefrontal cortex (dmPFC). We also imaged the apical dendrites of dmPFC pyramidal neurons. Images were taken daily in separate cohorts of juvenile (P24-P28) and young adult mice (P64-P68), ages where we have previously discovered differences in dmPFC dependent decision-making. Dendritic spines were pruned across this peri-adolescent period, while BLA and OFC afferents followed alternate developmental trajectories. OFC boutons showed no decrease in density, but did show a decrease in daily bouton gain and loss with age. BLA axons showed an increase in both bouton density and daily bouton gain at the later age, suggesting a delayed window of enhanced plasticity. Our findings reveal projection specific maturation of synaptic structures within a single frontal region and suggest that stabilization is a more general characteristic of maturation than pruning.
            Cover page: Long-range orbitofrontal and amygdala axons show divergent patterns of maturation in the frontal cortex across adolescence
            • Article
            • Peer Reviewed
            UC Berkeley Previously Published Works (2017)
            Postnatal brain development is studded with sensitive periods during which experience dependent plasticity is enhanced. This enables rapid learning from environmental inputs and reorganization of cortical circuits that matches behavior with environmental contingencies. Significant headway has been achieved in characterizing and understanding sensitive period biology in primary sensory cortices, but relatively little is known about sensitive period biology in associative neocortex. One possible mediator is the onset of puberty, which marks the transition to adolescence, when animals shift their behavior toward gaining independence and exploring their social world. Puberty onset correlates with reduced behavioral plasticity in some domains and enhanced plasticity in others, and therefore may drive the transition from juvenile to adolescent brain function. Pubertal onset is also occurring earlier in developed nations, particularly in unserved populations, and earlier puberty is associated with vulnerability for substance use, depression and anxiety. In the present article we review the evidence that supports a causal role for puberty in developmental changes in the function and neurobiology of the associative neocortex. We also propose a model for how pubertal hormones may regulate sensitive period plasticity in associative neocortex. We conclude that the evidence suggests puberty onset may play a causal role in some aspects of associative neocortical development, but that further research that manipulates puberty and measures gonadal hormones is required. We argue that further work of this kind is urgently needed to determine how earlier puberty may negatively impact human health and learning potential. This article is part of a Special Issue entitled SI: Adolescent plasticity.
              Cover page: Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex?
              • Article
              • Peer Reviewed
              UC Berkeley Previously Published Works (2019)
              Neuromodulation plays a critical role in brain function in both health and disease, and new tools that capture neuromodulation with high spatial and temporal resolution are needed. Here, we introduce a synthetic catecholamine nanosensor with fluorescent emission in the near infrared range (1000-1300 nm), near infrared catecholamine nanosensor (nIRCat). We demonstrate that nIRCats can be used to measure electrically and optogenetically evoked dopamine release in brain tissue, revealing hotspots with a median size of 2 µm. We also demonstrated that nIRCats are compatible with dopamine pharmacology and show D2 autoreceptor modulation of evoked dopamine release, which varied as a function of initial release magnitude at different hotspots. Together, our data demonstrate that nIRCats and other nanosensors of this class can serve as versatile synthetic optical tools to monitor neuromodulatory neurotransmitter release with high spatial resolution.
                Cover page: Imaging striatal dopamine release using a nongenetically encoded near infrared fluorescent catecholamine nanosensor
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