Brian Sweis - Academia.edu (original) (raw)

Papers by Brian Sweis

How the brain processes information when making decisions depends on how that information is stor... more How the brain processes information when making decisions depends on how that information is stored. Distinct neural circuits are capable of storing information in many different ways that are better suited for different situations. The decision-making processes that access those different bits of stored information are not singular and occupy separable neural circuits, each of which can operate in parallel with one another, and each of which can confer different information processing properties based on the neural constraints within which a given computation resides. Such is the framework of recent theories in neuroeconomics, which suggest that decisions are multi-faceted and action-selection processes can arise from fundamentally distinct circuit-specific neural computations. In this thesis, I present a body of work that takes a neuroeconomics approach through a series of experiments that reveal the complexities of multiple, parallel decision-making systems through complex behaviors by moving beyond simple tests of value. In the first half of this thesis, I demonstrate how complex behavioral computations can resolve fundamentally distinct valuation algorithms thought to reside in separable neural circuits. I then translate this approach between human and non-human rodent animal models in order to reveal how multiple, parallel decision-making systems are conserved across species over evolution. In the second half of this thesis, I demonstrate the utility of behavioral economics in disease-relevant and circuit-based studies. If multiple, parallel decision-making processes are thought to be intimately related to the heterogeneous ways in which information can be stored in separable neural circuits, I examine how addiction – a disease which is thought to be a disorder of the neurobiological mechanisms of learning and memory – might alter how stored information is processed in separable decision-making systems uniquely using a mouse model of two different forms of addiction. In doing so, I demonstrate how different forms of addiction give rise to unique, lasting vulnerabilities in fundamentally distinct decision-making computations. These discoveries can aid in resolving neuropsychiatric disease heterogeneity by moving beyond simple tests of value where complex behaviors that are measured can more accurately reflect the neurally distinct computations that underlie those behaviors. Finally, I take a neuromodulation approach and directly alter the strength of synaptic transmission in a circuit-specific manner using optogenetics in mice tested in this neuroeconomic framework. I demonstrate how plasticity alterations in projections between the infralimbic cortex and the nucleus accumbens are capable of giving rise to long-lasting disruptions of self-control related decision processes in a foraging valuation algorithm independent of and separate from a deliberative valuation algorithm measured within the same trial. Furthermore, I developed a novel plasticity measurement tool that is assayed at the neuronal population ensemble level and reveals individual differences in separable decision processes. The second half of the thesis demonstrates a potential biomarker to target as a circuit-computation-specific therapeutic intervention tailored to those types of decision-making dysfunctions. Taken together, I present a body of work in this thesis that demonstrates the utility of moving beyond simple tests of value in order to resolve the computational complexity of decision making.

The nucleus accumbens shell (NAcSh) is involved in reward valuation. Excitatory projections from ... more The nucleus accumbens shell (NAcSh) is involved in reward valuation. Excitatory projections from infralimbic cortex (IL) to NAcSh undergo synaptic remodeling in rodent models of addiction and enable the extinction of disadvantageous behaviors. However , how the strength of synaptic transmission of the IL–NAcSh circuit affects decision-making information processing and reward valuation remains unknown, particularly because these processes can conflict within a given trial and particularly given recent data suggesting that decisions arise from separable information-processing algorithms. The approach of many neuromodulation studies is to disrupt information flow during ongoing behaviors; however, this limits the interpretation of endogenous encoding of computational processes. Furthermore, many studies are limited by the use of simple behavioral tests of value which are unable to dissociate neurally distinct decision-making algorithms. We optogenetically altered the strength of synaptic transmission between glutamatergic IL–NAcSh projections in mice trained on a neuroeconomic task capable of separating multiple valuation processes. We found that induction of long-term depression in these synapses produced lasting changes in foraging processes without disrupting deliberative processes. Mice displayed inflated reevalu-ations to stay when deciding whether to abandon continued reward-seeking investments but displayed no changes during initial commitment decisions. We also developed an ensemble-level measure of circuit-specific plasticity that revealed individual differences in foraging valuation tendencies. Our results demonstrate that alterations in projection-specific synaptic strength between the IL and the NAcSh are capable of augmenting self-control economic valuations within a particular decision-making modality and suggest that the valuation mechanisms for these multiple decision-making modalities arise from different circuits.

Sunk costs are irrecoverable investments that should not influence decisions because decisions sh... more Sunk costs are irrecoverable investments that should not influence decisions because decisions should be made based on expected future consequences. Both human and non-human animals can show sensitivity to sunk costs, but reports across species are inconsistent. In a temporal context, a sensitivity to sunk costs arises when an individual resists ending an activity, even if it seems unproductive, because of the time already invested. In two novel, parallel foraging tasks, we find that mice, rats, and humans show similar sensitivities to sunk costs in their decision-making. Surprisingly, sensitivity to time invested accrued only after an initial decision had been made. These findings suggest sensitivity to temporal sunk costs lies in a vulnerability distinct from deliberation processes, and that this distinction is present across species.

Background: Hyperglycemia is common in extremely low gestational age newborns (ELGAN) and is asso... more Background: Hyperglycemia is common in extremely low gestational age newborns (ELGAN) and is associated with increased mortality and morbidity, including abnormal neurodevelopment. Hippocampus-mediated cognitive
deficits are common in this population, but the specific effects of hyperglycemia on the developing hippocampus are not known.

Methods: The objective of this study was to determine the acute and long-term effects of hyperglycemia on the developing hippocampus in neonatal rats using a streptozotocin (STZ)-induced model of hyperglycemia. STZ was
injected on postnatal day (P) 2, and littermates in the control group were injected with an equivalent volume of citrate buffer. The acute effects of hyperglycemia on markers of oxidative stress, inflammatory cytokines, microglial activation, and reactive astrocytosis in the hippocampus were determined in the brain tissue collected on P6. The long-term effects on hippocampus-mediated behavior and hippocampal dendrite structure were determined on P90.

Results: On P6, the transcript and protein expression of markers of oxidative stress and inflammatory cytokines, including the CXCL10/CXCR3 pathway, were upregulated in the hyperglycemia group. Histological evaluation revealed microglial activation and astrocytosis. The long-term assessment on P90 demonstrated abnormal performance in Barnes maze neurobehavioral testing and altered dendrite structure in the hippocampus of formerly hyperglycemic rats.

Conclusions: Neonatal hyperglycemia induces CXCL10/CXCR3 signaling, microglial activation, and astrocytosis in the rat hippocampus and alters long-term synaptogenesis and behavior. These results may explain the hippocampus-specific cognitive deficits common in ELGAN who experience neonatal hyperglycemia.

The elevated plus maze (EPM) is used to assess anxiety in rodents. Beam-walking tasks are used to... more The elevated plus maze (EPM) is used to assess anxiety in rodents. Beam-walking tasks are used to assess vestibulomotor function. Brain injury in rodents can disrupt performance on both of these tasks. Developing novel paradigms that integrate tasks like these can reduce the need for multiple tests when attempting to assess multiple behaviors in the same animal. Using adult male rats, we evaluated the use of a modified beam-walking (MBW) apparatus as a surrogate indicator for anxiety. We used a model of blast-induced traumatic brain injury (bTBI). A total of 39 rats were assessed before and at 3, 6, 24, 72, and 168 h either post-bTBI (n = 33) or no-injury (n = 6) using both EPM and MBW. A novel anxiety index was calculated that encompassed peeks and re-emergences on MBW. The proposed MBW anxiety index was compared with the standard anxiety index calculated from exploration into different sections of EPM. Post-bTBI, rats had an increased anxiety index when measured using EPM. Similarly, they peeked or fully emerged less out of the safe box on MBW. It was found that this novel MBW anxiety index captured similar aspects of behavior when compared to the standard anxiety index obtained from EPM. Further, these effects were dissociated from the effects of bTBI on motor function simultaneously measured on MBW. Over the course of 168 h post-bTBI, rats gradually recovered on both EPM and MBW. The MBW apparatus succeeded at capturing and dissociating two separate facets of rat behavior, motor function and anxiety, simultaneously.

The use of rodent strokemodels allowfor the understanding of stroke pathophysiology. There is cur... more The use of rodent strokemodels allowfor the understanding of stroke pathophysiology. There is currently no gold standard neurological assessment to measure deficits and recovery from stroke in rodent models. Agreement on a universal preclinical stroke scale allows for comparison of the outcomes among conducted studies. The present study aimed to compare three routinely used neurological assessments in rodent studies (i.e., Garcia, Modo, and Longa) to determine which is most effective for accurately and consistently quantifying neurological deficits in the context of focal middle cerebral artery occlusion (MCAo) in rats. Focal MCAo was induced in 22 maleWistar rats using a novel transfemoral approach. Rodents were assessed for neurological deficit pre-injury as well as 3 and 24 h post-injury. Data was analyzed to determine Pearson correlation coefficients in addition to McNemar's χ2 values between each pair of neurological assessments. All three stroke scales, Garcia, Modo, and Longa, showed
statistically significant changes between the baseline and the 3-hour neurological assessments. A trend towards neurological recovery was observed in all three stroke scales between the 3 and 24-hour endpoints. The three scales were highly correlated with each other, with Garcia and Modo having the strongest correlation. Of the three pairwise analyses, the comparison between the Garcia and Longa tests demonstrated the highest McNemar's χ2 value, indicating leastmarginal homogeneity between these two tests. The combination of high correlation between Garcia andModo tests alongwith greatestmarginal heterogeneity observed between the Garcia and Longa test lead us to recommend the use of Garcia and Longa neurological scales when researchers are hoping to capture the broadest range of neurological factors using only two stroke scales.

Chronic stress has been shown to impair memory, however, the extent to which memory can be impair... more Chronic stress has been shown to impair memory,
however, the extent to which memory can be impaired
is often variable across individuals. Predisposed differences
in particular traits, such as anxiety, may reveal underlying
neurobiological mechanisms that could be driving individual
differences in sensitivity to stress and, thus, stress resiliency.
Such pre-morbid characteristics may serve as early
indicators of susceptibility to stress. Neuropeptide Y (NPY)
and enkephalin (ENK) are neurochemical messengers of
interest implicated in modulating anxiety and motivation circuitry;
however, little is known about how these neuropeptides
interact with stress resiliency and memory. In this
experiment, adult male rats were appetitively trained to
locate sugar rewards in a motivation-based spatial memory
task before undergoing repeated immobilization stress and
then being tested for memory retention. Anxiety-related
behaviors, among other characteristics, were monitored
longitudinally. Results indicated that stressed animals
which showed little to no impairments in memory poststress
(i.e., the more stress-resilient individuals) exhibited
lower anxiety levels prior to stress when compared to
stressed animals that showed large deficits in memory
(i.e., the more stress-susceptible individuals). Interestingly,
all stressed animals, regardless of memory change, showed
reduced body weight gain as well as thymic involution, suggesting
that the effects of stress on metabolism and the
immune system were dissociated from the effects of stress
on higher cognition, and that stress resiliency seems to be
domain-specific rather than a global characteristic within
an individual. Neurochemical analyses revealed that NPY
in the hypothalamus and amygdala and ENK in the nucleus
accumbens were modulated differentially between stressresilient
and stress-susceptible individuals, with elevated
expression of these neuropeptides fostering anxiolytic and
pro-motivation function, thus driving cognitive resiliency
in a domain-specific manner. Findings suggest that such
neurochemical markers may be novel targets for pharmacological
interventions that can serve to prevent or ameliorate
the negative effects of stress on memory.

Inhibitory control is an important aspect of analogical reasoning critically dependent on prefron... more Inhibitory control is an important aspect of analogical reasoning critically dependent on prefrontal cortex. We used a novel visual analogy paradigm with scalp electroencephalography (EEG) to explore several ways the brain uses inhibitory control to perform analogy. Previous studies have suggested that inhibitory control helps to manage working memory, so we used a separate task to measure individual differences in working-memory span to help us interpret differences in inhibitory control during reasoning. We found evidence that low working-memory span individuals likely lacked the necessary inhibitory control to keep unattended relations from entering visuospatial working memory early in processing. We also found that a late frontal event-related potential sensitive to relational distraction was differentially modulated in high and low working memory span individuals. These findings provide additional evidence for the importance of inhibitory control during analogical processing.

Regret can be defined as the subjective experience of recognizing that one has made a mistake and... more Regret can be defined as the subjective experience of recognizing that one has made a mistake and that a better alternative could have been selected. The experience of regret is thought to carry negative utility. This typically takes two distinct forms: augmenting immediate postregret valuations to make up for losses, and augmenting long-term changes in decision-making strategies to avoid future instances of regret altogether. While the short-term changes in valuation have been studied in human psychology, economics, neuroscience, and even recently in nonhuman-primate and rodent neurophysiology, the latter long-term process has received far less attention, with no reports of regret avoidance in nonhuman decision-making paradigms. We trained 31 mice in a novel variant of the Restaurant Row economic decision-making task, in which mice make decisions of whether to spend time from a limited budget to achieve food rewards of varying costs (delays). Importantly, we tested mice longitudinally for 70 consecutive days, during which the task provided their only source of food. Thus, decision strategies were interdependent across both trials and days. We separated principal commitment decisions from secondary reevaluation decisions across space and time and found evidence for regret-like behaviors following change-of-mind decisions that corrected prior economically disadvantageous choices. Immediately following change-of-mind events, subsequent decisions appeared to make up for lost effort by altering willingness to wait, decision speed, and pellet consumption speed, consistent with past reports of regret in rodents. As mice were exposed to an increasingly reward-scarce environment, we found they adapted and refined distinct economic decision-making strategies over the course of weeks to maximize reinforcement rate. However, we also found that even without changes in reinforcement rate, mice transitioned from an early strategy rooted in foraging to a strategy rooted in deliberation and planning that prevented future regret-inducing change-of-mind episodes from occurring. These data suggest that mice are learning to avoid future regret, independent of and separate from reinforcement rate maximization.

Addiction is considered to be a neurobiological disorder of learning and memory because addiction... more Addiction is considered to be a neurobiological disorder of learning and memory because addiction is capable of producing lasting changes in the brain. Recovering addicts chronically struggle with making poor decisions that ultimately lead to relapse, suggesting a view of addiction also as a neurobiological disorder of decision-making information processing. How the brain makes decisions depends on how decision-making processes access information stored as memories in the brain. Advancements in circuit-dissection tools and recent theories in neuroeconomics suggest that neurally dissociable valuation processes access distinct memories differently, and thus are uniquely susceptible as the brain changes during addiction. If addiction is to be considered a neurobiological disorder of memory, and thus decision-making, the heterogeneity with which information is both stored and processed must be taken into account in addiction studies. Addiction etiology
can vary widely from person to person. We propose that addiction is not a single disease, nor simply a disorder of learning and memory, but rather a collection of symptoms of heterogeneous neurobiological diseases of distinct circuit-computation-specific decision-making processes.

Neuroeconomic theories propose changes in decision making drive relapse in recovering drug addict... more Neuroeconomic theories propose changes in decision making drive relapse in recovering drug addicts, resulting in continued drug use despite stated wishes not to. Such conflict is thought to arise from multiple valuation systems dependent on separable neural components, yet many neurobiology of addiction studies employ only simple tests of value. Here, we tested in mice how prolonged abstinence from different drugs affects behavior in a neuroeconomic foraging task that reveals multiple tests of value. Abstinence from repeated cocaine and morphine disrupts separable decision-making processes. Cocaine alters deliberation-like behavior prior to choosing a preferred though economically unfavorable offer, while morphine disrupts re-evaluations after rapid initial decisions. These findings suggest that different drugs have long-lasting effects precipitating distinct decision-making vulnerabilities. Our approach can guide future refinement of decision-making behavioral paradigms and highlights how grossly similar behavioral maladaptations may mask multiple underlying, parallel, and dis-sociable processes that treatments for addiction could potentially target.