Decreased home cage movement and oromotor impairments in adult \u3ci\u3eFmr1\u3c/i\u3e-KO mice

Fragile X syndrome (FXS) is a common inherited disorder that significantly impacts family and patient day-to-day living across the entire lifespan. The childhood and adolescent behavioral consequences of FXS are well-appreciated. However, there are significantly fewer studies (except those examining psychiatric comorbidities) assessing behavioral phenotypes seen in adults with FXS. Mice engineered with a genetic lesion of Fmr1 recapitulate important molecular and neuroanatomical characteristics of FXS, and provide a means to evaluate adult behavioral phenotypes associated with FXS. We give the first description of baseline behaviors including feeding, drinking, movement, and their circadian rhythms; all observed over 16 consecutive days following extensive environmental habituation in adult Fmr1-KO mutant mice. We find no genotypic changes in mouse food ingestion, feeding patterns, metabolism, or circadian patterns of movement, feeding, and drinking. After habituation, Fmr1-KO mice demonstrate significantly less daily movement during their active phase (the dark cycle). However, Fmr1-KO mice have more bouts of activity during the light cycle compared to wildtypes. In addition, Fmr1-KO mice demonstrate significantly less daily water ingestion during the circadian dark cycle, and this reduction in water intake is accompanied by a decrease in the amount of water ingested per lick. The observed water ingestion and circadian phenotypes noted in Fmr1-KO mice recapitulate known clinical aspects previously described in FXS. The finding of decreased movement in Fmr1-KO mice is novel, and suggests a dissociation between baseline and novelty-evoked activity for Fmr1-KO mice

A Low-Cost, Reliable, High-Throughput System for Rodent Behavioral Phenotyping in a Home Cage Environment

Inexpensive, high-throughput, low maintenance systems for precise temporal and spatial measurement of mouse home cage behavior (including movement, feeding, and drinking) are required to evaluate products from large scale pharmaceutical design and genetic lesion programs. These measurements are also required to interpret results from more focused behavioral assays. We describe the design and validation of a highly-scalable, reliable mouse home cage behavioral monitoring system modeled on a previously described, one-ofa- kind system [1]. Mouse position was determined by solving static equilibrium equations describing the force and torques acting on the system strain gauges; feeding events were detected by a photobeam across the food hopper, and drinking events were detected by a capacitive lick sensor. Validation studies show excellent agreement between mouse position and drinking events measured by the system compared with video-based observation – a gold standard in neuroscience

Age‐related changes in cerebellar and hypothalamic function accompany non‐microglial immune gene expression, altered synapse organization, and excitatory amino acid neurotransmission deficits

We describe age-related molecular and neuronal changes that disrupt mobility or energy balance based on brain region and genetic background. Compared to young mice, aged C57BL/6 mice exhibit marked locomotor (but not energy balance) impairments. In contrast, aged BALB mice exhibit marked energy balance (but not locomotor) impairments. Age-related changes in cerebellar or hypothalamic gene expression accompany these phenotypes. Aging evokes upregulation of immune pattern recognition receptors and cell adhesion molecules. However, these changes do not localize to microglia, the major CNS immunocyte. Consistent with a neuronal role, there is a marked age-related increase in excitatory synapses over the cerebellum and hypothalamus. Functional imaging of these regions is consistent with age-related synaptic impairments. These studies suggest that aging reactivates a developmental program employed during embryogenesis where immune molecules guide synapse formation and pruning. Renewed activity in this program may disrupt excitatory neurotransmission, causing significant behavioral deficits

Decreased home cage movement and oromotor impairments in adult \u3ci\u3eFmr1\u3c/i\u3e-KO mice

Fragile X syndrome (FXS) is a common inherited disorder that significantly impacts family and patient day-to-day living across the entire lifespan. The childhood and adolescent behavioral consequences of FXS are well-appreciated. However, there are significantly fewer studies (except those examining psychiatric comorbidities) assessing behavioral phenotypes seen in adults with FXS. Mice engineered with a genetic lesion of Fmr1 recapitulate important molecular and neuroanatomical characteristics of FXS, and provide a means to evaluate adult behavioral phenotypes associated with FXS. We give the first description of baseline behaviors including feeding, drinking, movement, and their circadian rhythms; all observed over 16 consecutive days following extensive environmental habituation in adult Fmr1-KO mutant mice. We find no genotypic changes in mouse food ingestion, feeding patterns, metabolism, or circadian patterns of movement, feeding, and drinking. After habituation, Fmr1-KO mice demonstrate significantly less daily movement during their active phase (the dark cycle). However, Fmr1-KO mice have more bouts of activity during the light cycle compared to wildtypes. In addition, Fmr1-KO mice demonstrate significantly less daily water ingestion during the circadian dark cycle, and this reduction in water intake is accompanied by a decrease in the amount of water ingested per lick. The observed water ingestion and circadian phenotypes noted in Fmr1-KO mice recapitulate known clinical aspects previously described in FXS. The finding of decreased movement in Fmr1-KO mice is novel, and suggests a dissociation between baseline and novelty-evoked activity for Fmr1-KO mice

Synergistic impairment of glucose homeostasis in ob/ob mice lacking functional serotonin 2C receptors.

To investigate how serotonin and leptin interact in the regulation of energy balance and glucose homeostasis, we generated a genetic mouse model, the OB2C mouse, which lacks functional serotonin 2C receptors and the adipocyte hormone leptin. The OB2C mice exhibited a dramatic diabetes phenotype, evidenced by a synergistic increase in serum glucose levels and water intake. The severity of the animals' diabetes phenotype would not have been predicted from the phenotypic characterization of mice bearing mutations of either the leptin (OB mutant mice) or the serotonin 2C receptor gene (2C mutant mice). The synergistic impairment in glucose homeostasis developed at an age when OB2C mice did not differ in body weight from OB mice, suggesting that this impairment was not an indirect consequence of increased adiposity. We also demonstrated that the improvement in glucose tolerance in wild-type mice treated with the serotonin releaser and reuptake inhibitor fenfluramine was blunted in 2C mutant mice. These pharmacological and genetic findings provide evidence that the serotonin 2C receptor has direct effects on glucose homeostasis

A Smartphone-Based Self-Management Intervention for Individuals with Bipolar Disorder (LiveWell): Qualitative Study on User Experiences of the Behavior Change Process

BackgroundBipolar disorder is a severe mental illness characterized by recurrent episodes of depressed, elevated, and mixed mood states. The addition of psychotherapy to pharmacological management can decrease symptoms, lower relapse rates, and improve quality of life; however, access to psychotherapy is limited. Mental health technologies such as smartphone apps are being studied as a means to increase access to and enhance the effectiveness of adjunctive psychotherapies for bipolar disorder. Individuals with bipolar disorder find this intervention format acceptable, but our understanding of how people utilize and integrate these tools into their behavior change and maintenance processes remains limited. ObjectiveThe objective of this study was to explore how individuals with bipolar disorder perceive and utilize a smartphone intervention for health behavior change and maintenance. MethodsIndividuals with bipolar disorder were recruited via flyers placed at university-affiliated and private outpatient mental health practices to participate in a pilot study of LiveWell, a smartphone-based self-management intervention. At the end of the study, all participants completed in-depth qualitative exit interviews. The behavior change framework developed to organize the intervention design was used to deductively code behavioral targets and determinants involved in target engagement. Inductive coding was used to identify themes not captured by this framework. ResultsIn terms of behavioral targets, participants emphasized the importance of managing mood episode–related signs and symptoms. They also discussed the importance of maintaining regular routines, sleep duration, and medication adherence. Participants emphasized that receiving support from a coach as well as seeking and receiving assistance from family, friends, and providers were important for managing behavioral targets and staying well. In terms of determinants, participants stressed the important role of monitoring for their behavior change and maintenance efforts. Monitoring facilitated self-awareness and reflection, which was considered valuable for staying well. Some participants also felt that the intervention facilitated learning information necessary for managing bipolar disorder but others felt that the information provided was too basic. ConclusionsIn addition to addressing acceptability, satisfaction, and engagement, a person-based design of mental health technologies can be used to understand how people experience the impact of these technologies on their behavior change and maintenance efforts. This understanding may then be used to guide ongoing intervention development. The participants’ perceptions aligned with the intervention’s primary behavioral targets and use of a monitoring tool as a core intervention feature. Participant feedback further indicates that developing additional content and tools to address building and engaging social support may be an important avenue for improving LiveWell. A comprehensive behavior change framework to understand participant perceptions of their behavior change and maintenance efforts may help facilitate ongoing intervention development