The forced swim test (FST) measures coping strategy to an acute inescapable stress and thus provides unique insight into the neural limb of the stress response. Stress, particularly chronic stress, is a contributing factor to depression in humans and depression is associated with altered response to stress. In addition, drugs that are effective antidepressants in humans typically promote active coping strategy in the FST. As a consequence, passive coping in the FST has become loosely equated with depression and is often referred to as “depression-like” behavior. This terminology oversimplifies complex biology and misrepresents both the utility and limitations of the FST. The FST provides little construct- or face-validity to support an interpretation as “depression-like” behavior. While stress coping and the FST are arguably relevant to depression, there are likely many factors that can influence stress coping strategy. Importantly, there are other neuropsychiatric disorders characterized by altered responses to stress and difficulty in adapting to change. One of these is autism spectrum disorder (ASD), and several mouse genetic models of ASD exhibit altered stress-coping strategies in the FST. Here we review evidence that argues a more thoughtful consideration of the FST, and more precise terminology, would benefit the study of stress and disorders characterized by altered response to stress, which include but are not limited to depression.
Chronic nicotine exposure during adolescence induces dendritic remodeling of medium spiny neurons (MSNs) in the nucleus accumbens (NAcc) shell. While nicotine-induced dendritic remodeling has frequently been described as persistent, the trajectory of dendrite remodeling is unknown. Specifically, no study to date has characterized the structural plasticity of dendrites in the NAcc immediately following chronic nicotine, leaving open the possibility that dendrite remodeling emerges gradually over time. Further, the neuropharmacological mechanisms through which nicotine induces dendrite remodeling are not well understood. To address these questions, rats were co-administered chronic nicotine (0.5 mg/kg) and the D1-dopamine receptor (D1DR) antagonist SCH-23390 (0.05 mg/kg) subcutaneously every other day during adolescence. Brains were then processed for Golgi-Cox staining either 1 day or 21 days following drug exposure and dendrites from MSNs in the NAcc shell digitally reconstructed in 3D. Spine density was also measured at both time points. Our morphometric results show (1) the formation of new dendritic branches and spines 1 day following nicotine exposure, (2) new dendritic branches, but not spine density, remains relatively stable for at least 21 days, (3) the co-administration of SCH-23390 completely blocked nicotine-induced dendritic remodeling of MSNs at both early and late time points, suggesting the formation of new dendritic branches in response to nicotine is D1DR-dependent, and (4) SCH-23390 failed to block nicotine-induced increases in spine density. Overall this study provides new insight into how nicotine influences the normal trajectory of adolescent brain development and demonstrates a persistent form of nicotine-induced neuroplasticity in the NAcc shell that develops rapidly and is D1DR dependent.
In humans a chromosomal hemideletion of the 16p11.2 region results in variable neurodevelopmental deficits including developmental delay, intellectual disability and features of autism spectrum disorder (ASD). Serotonin is implicated in ASD but its role remains enigmatic. In this study we sought to determine if and how abnormalities in serotonin neurotransmission could contribute to the behavioral phenotype of the 16p11.2 deletion syndrome in a mouse model (Del mouse). Since ASD is frequently associated with altered response to acute stress and stress may exacerbate repetitive behavior in ASD, we studied the Del mouse behavior in the context of an acute stress using the forced swim test, a paradigm well characterized with respect to serotonin. Del mice perseverated with active coping (swimming) in the forced swim test and failed to adopt passive coping strategies with time as did their wild-type (WT) littermates. Analysis of monoamine content by HPLC provided evidence for altered endogenous serotonin neurotransmission in Del mice while there was no effect of genotype on any other monoamine. Moreover we found that Del mice were highly sensitive to the 5-HT2A antagonists M100907, which at a dose of 0.1 mg/kg normalized their level of active coping and restored the gradual shift to passive coping in the forced swim test. Supporting evidence for altered endogenous serotonin signaling was provided by observations of additional ligand effects including altered forebrain Fos expression. Taken together, these observations indicate notable changes in endogenous serotonin signaling in 16p11.2 deletion mice and support the therapeutic utility of 5-HT2A receptor antagonists.
Human genetic variation in the gene CACNA1C, which codes for the alpha-1c subunit of Cav1.2 L-type calcium channels (LTCCs), has been broadly associated with enhanced risk for neuropsychiatric disorders including major depression, bipolar and schizophrenia. Little is known about the specific neural circuits through which CACNA1C and Cav1.2 LTCCs impact disease etiology. However, serotonin (5-HT) neurotransmission has been consistently implicated in these neuropsychiatric disorders and Cav1.2 LTCCs may influence 5-HT neuron activity during relevant behavioral states such as stress. We utilized a temporally controlled and 5-HT neuron specific Cacna1c knockout mouse model to assess stress-coping behavior using the forced swim test and dorsal raphe (DR) 5-HT neuron Fos activation. Furthermore, we assessed 5-HT1A receptor function and feedback inhibition of the DR following administration of the 5-HT1A antagonist WAY-100635. We find that 5-HT neuron Cacna1c knockout disrupts active-coping behavior in the forced swim test and that this behavioral effect is rescued by blocking 5-HT1A receptors. Moreover, Cacna1c knockout mice display enhanced Fos expression in caudal DR 5-HT neurons and an enhanced response to a 5-HT1A receptor antagonist in rostral DR 5-HT neurons, indicating that loss of Cacna1c disrupts both 5-HT neuron activation and 5-HT1A dependent feedback inhibition across the caudal to rostral DR. Collectively, these results reveal an important role for 5-HT neuron Cav1.2 LTCCs in stress-coping behavior and 5-HT1A receptor function. This suggests that alterations in CACNA1C function or expression could influence the development or treatment of neuropsychiatric disorder through serotonergic mechanisms.
Polymorphism in the gene CACNA1C, encoding the pore-forming subunit of Cav1.2 L-type calcium channels, has one of the strongest genetic linkages to schizophrenia, bipolar disorder, and major depressive disorder: psychopathologies in which serotonin signaling has been implicated. Additionally, a gain-of-function mutation in CACNA1C is responsible for the neurodevelopmental disorder Timothy Syndrome that presents with prominent behavioral features on the autism spectrum. Given an emerging role for serotonin in the etiology of autism spectrum disorders, we investigate the relationship between Cav1.2 and the ascending serotonin system in the Timothy Syndrome type 2 (TS2-neo) mouse, which displays behavioral features consistent with the core triad of ASD. We find that TS2-neo mice exhibit enhanced serotonin tissue content and axon innervation of the dorsal striatum, as well as decreased serotonin turnover in the amygdala. These regionally specific alterations are accompanied by an enhanced active coping response during acute stress (forced-swim), serotonin neuron Fos-activity in the caudal dorsal raphe, and serotonin type 1A receptor dependent feedback-inhibition of the rostral DRN. Collectively, these results suggest that the global gain of function Cav1.2 mutation associated with Timothy Syndrome has pleotropic effects on the ascending serotonin system including neuroanatomical changes, regional differences in forebrain serotonin metabolism and feedback regulatory control mechanisms within the dorsal raphe. Altered activity of the ascending serotonin system continues to emerge as a common neural signature across several ASD mouse models, and the capacity for Cav1.2 L-type calcium channels to impact both serotonin structure and function has important implications for several neuropsychiatric conditions.
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