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The regulator of G-protein signaling 14 (RGS14) is a multifunctional signaling protein that regulates post synaptic plasticity in neurons. RGS14 is expressed in the brain regions essential for learning, memory, emotion, and stimulus-induced behaviors, including the basal ganglia, limbic system, and cortex. Behaviorally, RGS14 regulates spatial and object memory, female-specific responses to cued fear conditioning, and environmental- and psychostimulant-induced locomotion. At the cellular level, RGS14 acts as a scaffolding protein that integrates G protein, Ras/ERK, and calcium/calmodulin signaling pathways essential for spine plasticity and cell signaling, allowing RGS14 to naturally suppress long-term potentiation (LTP) and structural plasticity in hippocampal area CA2 pyramidal cells. Recent proteomics findings indicate that RGS14 also engages the actomyosin system in the brain, perhaps to impact spine morphogenesis. Of note, RGS14 is also a nucleocytoplasmic shuttling protein, where its role in the nucleus remains uncertain. Balanced nuclear import/export and dendritic spine localization are likely essential for RGS14 neuronal functions as a regulator of synaptic plasticity. Supporting this idea, human genetic variants disrupting RGS14 localization also disrupt RGS14’s effects on plasticity. This review will focus on the known and unexplored roles of RGS14 in cell signaling, physiology, disease and behavior.

Adolescence represents a developmental stage in which initiation of drug use typically occurs and is marked by dynamic neurobiological changes. These changes present a sensitive window during which perturbations to normative development lead to alterations in brain circuits critical for stress and emotional regulation as well as reward processing, potentially resulting in an increased susceptibility to psychopathologies. The occurrence of early life stress (ELS) is related to a greater risk for the development of substance use disorders (SUD) during adolescence. Studies using nonhuman primates (NHP) are ideally suited to examine how ELS may alter the development of neurobiological systems modulating the reinforcing effects of drugs, given their remarkable neurobiological, behavioral, and developmental homologies to humans. This review examines NHP models of ELS that have been used to characterize its effects on sensitivity to drug reinforcement, and proposes future directions using NHP models of ELS and drug abuse in an effort to develop more targeted intervention and prevention strategies for at risk clinical populations.

RationaleIn rodents, exposure to novel environments or psychostimulants promotes locomotor activity. Indeed, locomotor reactivity to novelty strongly predicts behavioral responses to psychostimulants in animal models of addiction. RGS14 is a plasticity restricting protein with unique functional domains that enable it to suppress ERK-dependent signaling as well as regulate G protein activity. Although recent studies show that RGS14 is expressed in multiple limbic regions implicated in psychostimulant- and novelty-induced hyperlocomotion, its function has been studied almost entirely in the context of hippocampal physiology and hippocampusdependent behaviors.ObjectiveWe sought to determine whether RGS14 modulates novelty- and psychostimulant-induced locomotion and neuronal activity.MethodsWe assessed Rgs14 knockout (RGS14 KO) mice and wild-type (WT) littermate controls using novelty-induced locomotion (NIL) and cocaine-induced locomotion (CIL) behavioral tests with subsequent quantification of c-fos and phosphorylated ERK (pERK) induction in limbic regions that express RGS14.ResultsCompared to WT controls, RGS14 KO mice exhibited attenuated locomotor responses in the NIL test, driven by avoidance of the center of the novel environment. By contrast, RGS14 KO mice demonstrated augmented peripheral locomotion in the CIL test conducted in either a familiar or novel environment. The absence of RGS14 enhanced induction of c-fos and pERK in the central amygdala and hippocampus (areas CA1 and CA2) when cocaine was administered in a novel environment.ConclusionsRGS14 regulates novelty- and psychostimulant-induced hyperlocomotion, particularly with respect to thigmotaxis. Further, our findings suggest RGS14 may reduce neuronal activity in discrete limbic subregions by inhibiting ERK-dependent signaling and transcription.

AcknowledgmentsWe thank C. Strauss for helpful editing of the manuscript.

RGS14 is a multifunctional scaffolding protein that is highly expressed within postsynaptic spines of pyramidal neurons in hippocampal area CA2. Known roles of RGS14 in CA2 include regulating G protein, H‐Ras/ERK, and calcium signaling pathways to serve as a natural suppressor of synaptic plasticity and postsynaptic signaling. RGS14 also shows marked postsynaptic expression in major structures of the limbic system and basal ganglia, including the amygdala and both the ventral and dorsal subdivisions of the striatum. In this review, we discuss the signaling functions of RGS14 and its role in postsynaptic strength (long‐term potentiation) and spine structural plasticity in CA2 hippocampal neurons, and how RGS14 suppression of plasticity impacts linked behaviors such as spatial learning, object memory, and fear conditioning. We also review RGS14 expression in the limbic system and basal ganglia and speculate on its possible roles in regulating plasticity in these regions, with a focus on behaviors related to emotion and motivation. Finally, we explore the functional implications of RGS14 in various brain circuits and speculate on its possible roles in certain disease states such as hippocampal seizures, addiction, and anxiety disorders.

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36Childhood maltreatment is among the most robust risk factors for subsequent psychiatric and 37 medical disorders, and data in humans and rodents suggest that effects of adverse childhood 38 experiences may be transmitted across generations. Recent indications for biological processes 39 underlying this transfer of experiential effects are intriguing; yet, their relevance in primates is 40 inconclusive due to limitations of current studies. In this study, we bridge research in rodent 41 models and humans with a natural non-human primate model on intergenerational effects of 42 childhood maltreatment. Using a unique, well-controlled, randomized cross-fostering design in 43 rhesus monkeys, we test the influence of ancestral maltreatment on molecular, neuroendocrine 44 and behavioral outcomes in offspring, and show that childhood maltreatment results in 45 transmission of information to the subsequent generation independent of behavioral 46 transmission. We further demonstrate differences in the offspring longitudinal DNA methylation 47 profile of the FKBP5 gene, an important regulator of the hypothalamus-pituitary-adrenal axis in 48 offspring of the maltreatment lineage compared to the control lineage. Finally, we show that 49 differences in FKBP5 methylation have functional effects on molecular, neuroendocrine and 50 behavioral outcomes in offspring of the maltreatment ancestral line, even if the infants were 51 never exposed to maltreatment nor interacted with their exposed ancestors. Although the 52 molecular mechanism underlying our observations remains unknown, our data point to a 53 potential germline-dependent effect. In summary, our data suggest that history of maltreatment 54 in primates can induce molecular and behavioral changes in a subsequent generation 55 independent of behavioral transmission that may influence risk for mental and physical diseases 56 across generations. 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 Exposure to childhood maltreatment is one the most important risk factors for a variety of 73 psychiatric disorders 1,2 . However, both human studies and animal models suggest that effects 74 of environmental experiences such as maltreatment extend beyond the affected individual, 75 influencing phenotypes in subsequent generations. This sparked a controversial discussion on 76 the prevalence of these phenomena, the underlying mechanisms and their biomedical relevance77 3-5 . Strong evidence exists for effects of environmental cues on offspring phenotypes when 78 exposed during in utero development 6-8 , or for the consequences of parental experience on 79 offspring phenotypes mediated by parental behavior 9 . More recently, experiments in rodents 80 suggested that pre-conceptional exposure to chemicals 10 , drugs 11 , nutritional abnormalities 12 81 and stress 13-15 can prompt intergenerational effects or even lead to transgenerational 82 inheritance of specific phenotypes 16 . These events seem independent of in utero perturbations 83 or behavioral transmission and point to p...