From Synapses to Circuits, Astrocytes Regulate Behavior

Astrocytes are non-neuronal cells that regulate synapses, neuronal circuits, and behavior. Astrocytes ensheath neuronal synapses to form the tripartite synapse where astrocytes influence synapse formation, function, and plasticity. Beyond the synapse, recent research has revealed that astrocyte influences on the nervous system extend to the modulation of neuronal circuitry and behavior. Here we review recent findings on the active role of astrocytes in behavioral modulation with a focus on in vivo studies, primarily in mice. Using tools to acutely manipulate astrocytes, such as optogenetics or chemogenetics, studies reviewed here have demonstrated a causal role for astrocytes in sleep, memory, sensorimotor behaviors, feeding, fear, anxiety, and cognitive processes like attention and behavioral flexibility. Current tools and future directions for astrocyte-specific manipulation, including methods for probing astrocyte heterogeneity, are discussed. Understanding the contribution of astrocytes to neuronal circuit activity and organismal behavior will be critical toward understanding how nervous system function gives rise to behavior.

Impact of adolescent intermittent ethanol exposure on interneurons and their surrounding perineuronal nets in adulthood.

Background: Binge alcohol exposure during adolescence results in long-lasting alterations in brain and behavior. For example, adolescent intermittent ethanol (AIE) exposure in rodents results in long-term loss of functional connectivity among prefrontal cortex (PFC) and striatal regions as well as a variety of neurochemical, molecular, and epigenetic alterations. Interneurons in the PFC and striatum play critical roles in behavioral flexibility and functional connectivity. For example, parvalbumin (PV) interneurons are known to contribute to neural synchrony, and cholinergic interneurons contribute to strategy selection. Furthermore, extracellular perineuronal nets (PNNs) surround some interneurons, particularly PV+ interneurons, to further regulate cellular plasticity. The effect of AIE exposure on expression of these markers within the PFC is not well understood. Methods: The present study tested the hypothesis that AIE exposure reduces expression of PV+ and ChAT+ interneurons in the adult PFC and striatum and increases related expression of PNNs (marked by binding of Wisteria Floribunda agglutinin lectin; WFA) in adulthood. Male rats were exposed to AIE (5 g/kg/day, 2-days-on/2-days-off, i.g., P25-P54) or water (CON), and brain tissue was harvested in adulthood (> P80). Immunohistochemistry and co-immunofluorescence were used to assess expression of ChAT, PV, and WFA labeling within the adult PFC and striatum following AIE exposure. Results: ChAT and PV interneuron numbers in the striatum and PFC were unchanged after AIE exposure. However, WFA labeling in the PFC of AIE-exposed rats was increased compared to CON rats. Moreover, significantly more PV neurons were surrounded by WFA labeling in AIE-exposed subjects relative to controls in both PFC subregions assessed: the orbitofrontal cortex (CON = 34%; AIE = 40%) and the medial PFC (CON = 10%; AIE = 14%). Conclusions: These findings indicate that while PV interneuron expression in the adult PFC and striatum is unaltered following AIE exposure, PNNs surrounding these neurons (indicated by extracellular WFA binding) are increased. This increase in PNNs may restrict plasticity of the ensheathed neurons, thus contributing to impaired microcircuitry in frontostriatal connectivity and related behavioral impairments.

Neural Circuits Underlying Behavioral Flexibility: Insights From Drosophila

Behavioral flexibility is critical to survival. Animals must adapt their behavioral responses based on changes in the environmental context, internal state, or experience. Studies in Drosophila melanogaster have provided insight into the neural circuit mechanisms underlying behavioral flexibility. Here we discuss how Drosophila behavior is modulated by internal and behavioral state, environmental context, and learning. We describe general principles of neural circuit organization and modulation that underlie behavioral flexibility, principles that are likely to extend to other species.

Behavioral flexibility is manipulatable and it improves flexibility and problem solving in a new context

Behavioral flexibility, the ability to adapt behavior to new circumstances, is thought to play an important role in a species' ability to successfully adapt to new environments and expand its geographic range. However, flexibility is rarely directly tested in species in a way that would allow us to determine how flexibility works and predictions a species' ability to adapt their behavior to new environments. We use great-tailed grackles (a bird species) as a model to investigate this question because they have rapidly expanded their range into North America over the past 140 years. We attempted to manipulate grackle flexibility using colored tube reversal learning to determine whether flexibility is generalizable across contexts (touchscreen reversal learning and multi-access box), whether it is repeatable within individuals and across contexts, and what learning strategies grackles employ. We found that we were able to manipulate flexibility: birds in the manipulated group took fewer trials to pass criterion with increasing reversal number, and they reversed a color preference in fewer trials by the end of their serial reversals compared to control birds who had only one reversal. Flexibility was repeatable within individuals (reversal), but not across contexts (from reversal to multi-access box). The touchscreen reversal experiment did not appear to measure what was measured in the reversal learning experiment with the tubes, and we speculate as to why. One third of the grackles in the manipulated reversal learning group switched from one learning strategy (epsilon-decreasing where they have a long exploration period) to a different strategy (epsilon-first where they quickly shift their preference). A separate analysis showed that the grackles did not use a particular strategy earlier or later in their serial reversals. Posthoc analyses using a model that breaks down performance on the reversal learning task into different components showed that learning to be attracted to an option (phi) more consistently correlated with reversal performance than the rate of deviating from learned attractions that were rewarded (lambda). This result held in simulations and in the data from the grackles: learning rates in the manipulated grackles doubled by the end of the manipulation compared to control grackles, while the rate of deviation slightly decreased. Grackles with intermediate rates of deviation in their last reversal, independently of whether they had gone through the serial reversal manipulation, solved fewer loci on the plastic and wooden multi-access boxes, and those with intermediate learning rates in their last reversal were faster to attempt a new locus on both multi-access boxes. This investigation allowed us to make causal conclusions rather than relying only on correlations: we manipulated reversal learning, which caused changes in a different flexibility measure (multi-access box switch times) and in an innovativeness measure (multi-access box loci solved), as well as validating that the manipulation had an effect on the cognitive ability we think of as flexibility. Understanding how behavioral flexibility causally relates to other traits will allow researchers to develop robust theory about what behavioral flexibility is and when to invoke it as a primary driver in a given context, such as a rapid geographic range expansion. Given our results, flexibility manipulations could be useful in training threatened and endangered species in how to be more flexible. If such a flexibility manipulation was successful, it could then change their behavior in this and other domains, giving them a better chance of succeeding in human modified environments.

In the Mindset of Opportunity: Proactive Mindset, Perceived Opportunities, and Role Attitudes

Perceiving roles as fulfilling goals offers motivational benefits to students, and yet the features of individuals or contexts that align with seeing such role opportunities have not been studied systematically. The current research investigated how these goal affordances are related to proactive mindset, or a person’s belief that they can shape their contexts. Three studies examined how variation in proactivity aligns with perceiving more communal and agentic goal opportunities in roles. Study 1 found that highly proactive college students (vs. less proactive students) tended to perceive their future careers as fulfilling communal and agentic goals, which predicted positive career attitudes. Study 2 replicated this association, while ruling out behavioral flexibility as accounting for the proactivity-positivity relationship. Study 3 experimentally tested whether growth-oriented contexts foster proactivity. Proactive mindset aligns with more expansive views of roles as fulfilling fundamental motives. These views, in turn, carry positive implications for one’s future career attitudes.

Repetitive Blast Exposure Increases Appetitive Motivation and Behavioral Inflexibility in Male Mice

Blast exposure (via detonation of high explosives) represents a major potential trauma source for Servicemembers and Veterans, often resulting in mild traumatic brain injury (mTBI). Executive dysfunction (e.g., alterations in memory, deficits in mental flexibility, difficulty with adaptability) is commonly reported by Veterans with a history of blast-related mTBI, leading to impaired daily functioning and decreased quality of life, but underlying mechanisms are not fully understood and have not been well studied in animal models of blast. To investigate potential underlying behavioral mechanisms contributing to deficits in executive functioning post-blast mTBI, here we examined how a history of repetitive blast exposure in male mice affects anxiety/compulsivity-like outcomes and appetitive goal-directed behavior using an established mouse model of blast mTBI. We hypothesized that repetitive blast exposure in male mice would result in anxiety/compulsivity-like outcomes and corresponding performance deficits in operant-based reward learning and behavioral flexibility paradigms. Instead, results demonstrate an increase in reward-seeking and goal-directed behavior and a congruent decrease in behavioral flexibility. We also report chronic adverse behavioral changes related to anxiety, compulsivity, and hyperarousal. In combination, these data suggest that potential deficits in executive function following blast mTBI are at least in part related to enhanced compulsivity/hyperreactivity and behavioral inflexibility and not simply due to a lack of motivation or inability to acquire task parameters, with important implications for subsequent diagnosis and treatment management.

Parental provisioning drives brain size in birds

Larger brains should be adaptive because they support numerous eco- and socio-cognitive benefits, but these benefits explain only a modest part of the interspecific variation in brain size. Notably underexplored are the high energetic costs of developing brains, and thus the possible role of parental provisioning in the evolution of adult brain size. We explore this idea in birds, which show considerable variation in both socio-ecological traits and the energy transfer from parents to offspring. Comparative analyses of 1,176 bird species show that the combination of adult body mass, mode of development at hatching, relative egg mass, and the time spent provisioning the young in combination strongly predict relative brain size across species. Adding adult eco- and socio-cognitive predictors only marginally adds explanatory value. We therefore conclude that parental provisioning enabled bird species to evolve into skill-intensive niches, reducing interspecific competition and consequently promoting survival prospects and population stability. Critically, parental provisioning also explains why precocial bird species have smaller brains than altricial ones. Finally, these results suggest that the cognitive adaptations that provide the behavioral flexibility to improve reproductive success and survival are intrinsically linked to successful parental provisioning. Our findings also suggest that the traditionally assessed cognitive abilities may not predict relative brain size.

Enriched Environment Modulates Sharp Wave-Ripple (SPW-R) Activity in Hippocampal Slices

Behavioral flexibility depends on neuronal plasticity which forms and adapts the central nervous system in an experience-dependent manner. Thus, plasticity depends on interactions between the organism and its environment. A key experimental paradigm for studying this concept is the exposure of rodents to an enriched environment (EE), followed by studying differences to control animals kept under standard conditions (SC). While multiple changes induced by EE have been found at the cellular-molecular and cognitive-behavioral levels, little is known about EE-dependent alterations at the intermediate level of network activity. We, therefore, studied spontaneous network activity in hippocampal slices from mice which had previously experienced EE for 10–15 days. Compared to control animals from standard conditions (SC) and mice with enhanced motor activity (MC) we found several differences in sharp wave-ripple complexes (SPW-R), a memory-related activity pattern. Sharp wave amplitude, unit firing during sharp waves, and the number of superimposed ripple cycles were increased in tissue from the EE group. On the other hand, spiking precision with respect to the ripple oscillations was reduced. Recordings from single pyramidal cells revealed a reduction in synaptic inhibition during SPW-R together with a reduced inhibition-excitation ratio. The number of inhibitory neurons, including parvalbumin-positive interneurons, was unchanged. Altered activation or efficacy of synaptic inhibition may thus underlie changes in memory-related network activity patterns which, in turn, may be important for the cognitive-behavioral effects of EE exposure.

Constitutive deficiency of the neurogenic hippocampal modulator AP2γ promotes anxiety-like behavior and cumulative memory deficits in mice from juvenile to adult periods

The transcription factor activating protein two gamma (AP2γ) is an important regulator of neurogenesis both during embryonic development as well as in the postnatal brain, but its role for neurophysiology and behavior at distinct postnatal periods is still unclear. In this work, we explored the neurogenic, behavioral, and functional impact of a constitutive and heterozygous AP2γ deletion in mice from early postnatal development until adulthood. AP2γ deficiency promotes downregulation of hippocampal glutamatergic neurogenesis, altering the ontogeny of emotional and memory behaviors associated with hippocampus formation. The impairments induced by AP2γ constitutive deletion since early development leads to an anxious-like phenotype and memory impairments as early as the juvenile phase. These behavioral impairments either persist from the juvenile phase to adulthood or emerge in adult mice with deficits in behavioral flexibility and object location recognition. Collectively, we observed a progressive and cumulative impact of constitutive AP2γ deficiency on the hippocampal glutamatergic neurogenic process, as well as alterations on limbic-cortical connectivity, together with functional behavioral impairments. The results herein presented demonstrate the modulatory role exerted by the AP2γ transcription factor and the relevance of hippocampal neurogenesis in the development of emotional states and memory processes.

Altered Cortico-Subcortical Network After Adolescent Alcohol Exposure Mediates Behavioral Deficits in Flexible Decision-Making

Behavioral flexibility, the ability to modify behavior according to changing conditions, is essential to optimize decision-making. Deficits in behavioral flexibility that persist into adulthood are one consequence of adolescent alcohol exposure, and another is decreased functional connectivity in brain structures involved in decision-making; however, a link between these two outcomes has not been established. We assessed effects of adolescent alcohol and sex on both Pavlovian and instrumental behaviors and resting-state functional connectivity MRI in adult animals to determine associations between behavioral flexibility and resting-state functional connectivity. Alcohol exposure impaired attentional set reversals and decreased functional connectivity among cortical and subcortical regions-of-interest that underlie flexible behavior. Moreover, mediation analyses indicated that adolescent alcohol-induced reductions in functional connectivity within a subnetwork of affected brain regions statistically mediated errors committed during reversal learning. These results provide a novel link between persistent reductions in brain functional connectivity and deficits in behavioral flexibility resulting from adolescent alcohol exposure.