mTORC2/rictor signaling disrupts dopamine-dependent behaviors via defects in striatal dopamine neurotransmission.

Disrupted neuronal protein kinase B (Akt) signaling has been associated with dopamine (DA)-related neuropsychiatric disorders, including schizophrenia, a devastating mental illness. We hypothesize that proper DA neurotransmission is therefore dependent upon intact neuronal Akt function. Akt is activated by phosphorylation of two key residues: Thr308 and Ser473. Blunted Akt phosphorylation at Ser473 (pAkt-473) has been observed in lymphocytes and postmortem brains of schizophrenia patients, and psychosis-prone normal individuals. Mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is a multiprotein complex that is responsible for phosphorylation of Akt at Ser473 (pAkt-473). We demonstrate that mice with disrupted mTORC2 signaling in brain exhibit altered striatal DA-dependent behaviors, such as increased basal locomotion, stereotypic counts, and exaggerated response to the psychomotor effects of amphetamine (AMPH). Combining in vivo and ex vivo pharmacological, electrophysiological, and biochemical techniques, we demonstrate that the changes in striatal DA neurotransmission and associated behaviors are caused, at least in part, by elevated D2 DA receptor (D2R) expression and upregulated ERK1/2 activation. Haloperidol, a typical antipsychotic and D2R blocker, reduced AMPH hypersensitivity and elevated pERK1/2 to the levels of control animals. By viral gene delivery, we downregulated mTORC2 solely in the dorsal striatum of adult wild-type mice, demonstrating that striatal mTORC2 regulates AMPH-stimulated behaviors. Our findings implicate mTORC2 signaling as a novel pathway regulating striatal DA tone and D2R signaling.

Neurobiological and behavioural outcomes of biofeedback-based training in autism: a randomized controlled trial.

The human brain has demonstrated the power to structurally change as a result of movement-based interventions. However, it is unclear whether these structural brain changes differ in autistic individuals compared to non-autistic individuals. The purpose of the present study was to pilot a randomized controlled trial to investigate brain, balance, autism symptom severity and daily living skill changes that result from a biofeedback-based balance intervention in autistic adolescents (13-17 years old). Thirty-four autistic participants and 28 age-matched non-autistic participants underwent diagnostic testing and pre-training assessment (neuroimaging, cognitive, autism symptom severity and motor assessments) and were then randomly assigned to 6 weeks of a balance-training intervention or a sedentary-control condition. After the 6 weeks, neuroimaging, symptom severity and motor assessments were repeated. Results found that both the autistic and non-autistic participants demonstrated similar and significant increases in balance times with training. Furthermore, individuals in the balance-training condition showed significantly greater improvements in postural sway and reductions in autism symptom severity compared to individuals in the control condition. Daily living scores did not change with training, nor did we observe hypothesized changes to the microstructural properties of the corticospinal tract. However, follow-up voxel-based analyses found a wide range of balance-related structures that showed changes across the brain. Many of these brain changes were specific to the autistic participants compared to the non-autistic participants, suggesting distinct structural neuroplasticity in response to balance training in autistic participants. Altogether, these findings suggest that biofeedback-based balance training may target postural stability challenges, reduce core autism symptoms and influence neurobiological change. Future research is encouraged to examine the superior cerebellar peduncle in response to balance training and symptom severity changes in autistic individuals, as the current study produced overlapping findings in this brain region.

Balance and the brain: A review of structural brain correlates of postural balance and balance training in humans.

BACKGROUND: Balance challenges are associated with not only the aging process but also a wide variety of psychiatric and neurological disorders. However, relatively little is known regarding the neural basis of balance and the effects of balance interventions on the brain. RESEARCH QUESTION: This review synthesizes the existing literature to answer the question: What are the key brain structures associated with balance? METHODS: This review examined 37 studies that assessed brain structures in relation to balance assessment or intervention. These studies provided 234 findings implicating 71 brain structures. The frequency of implication for each structure was examined based upon specific methodological parameters, including study design (assessment/intervention), type of balance measured (static/dynamic), population (clinical/non-clinical), and imaging analysis technique (region of interest [ROI]/voxel-based morphometry [VBM]). RESULTS: Although a number of structures were associated with balance across the brain, the most frequently implicated structures included the cerebellum, basal ganglia, thalamus, hippocampus, inferior parietal cortex, and frontal lobe regions. Findings in the cerebellum and brainstem were most common in studies with clinical populations, studies that used an ROI approach, and studies that measured dynamic balance. Findings in the frontal, occipital, and parietal regions were also more common in studies that measured dynamic compared to static balance. SIGNIFICANCE: While balance appears to be a whole-brain phenomenon, a subset of structures appear to play a key role in balance and are likely implicated in balance disorders. Some of these structures (i.e., the cerebellum, basal ganglia and thalamus) have a well-appreciated role in balance, whereas other regions (i.e., hippocampus and inferior parietal cortex) are not commonly thought to be associated with balance and therefore may provide alternative explanations for the neural basis of balance. Key avenues for future research include understanding the roles of all regions involved in balance across the lifespan and in different clinical populations.

Evidence for Brainstem Contributions to Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects one in 59 children in the United States. Although there is a mounting body of knowledge of cortical and cerebellar contributions to ASD, our knowledge about the early developing brainstem in ASD is only beginning to accumulate. Understanding how brainstem neurotransmission is implicated in ASD is important because many of this condition's sensory and motor symptoms are consistent with brainstem pathology. Therefore, the purpose of this review was to integrate epidemiological, behavioral, histological, neuroimaging, and animal evidence of brainstem contributions to ASD. Because ASD is a neurodevelopmental condition, we examined the available data through a lens of hierarchical brain development. The review of the literature suggests that developmental alterations of the brainstem could have potential cascading effects on cortical and cerebellar formation, ultimately leading to ASD symptoms. This view is supported by human epidemiology findings and data from animal models of ASD, showing that perturbed development of the brainstem substructures, particularly during the peak formation of the brainstem's monoaminergic centers, may relate to ASD or ASD-like behaviors. Furthermore, we review evidence from human histology, psychophysiology, and neuroimaging suggesting that brainstem development and maturation may be atypical in ASD and may be related to key ASD symptoms, such as atypical sensorimotor features and social responsiveness. From this review there emerges the need of future research to validate early detection of the brainstem-based somatosensory and psychophysiological behaviors that emerge in infancy, and to examine the brainstem across the life span, while accounting for age. In all, there is preliminary evidence for brainstem involvement in ASD, but a better understanding of the brainstem's role would likely pave the way for earlier diagnosis and treatment of ASD.

Biofeedback-Based, Videogame Balance Training in Autism.

The present study examined the effects of a visual-based biofeedback training on improving balance challenges in autism spectrum disorder (ASD). Twenty-nine youth with ASD (7-17 years) completed an intensive 6-week biofeedback-based videogame balance training. Participants exhibited training-related balance improvements that significantly accounted for postural-sway improvements outside of training. Participants perceived the training as beneficial and enjoyable. Significant moderators of training included milder stereotyped and ritualistic behaviors and better starting balance. Neither IQ nor BMI moderated training. These results suggest that biofeedback-based balance training is associated with balance improvements in youth with ASD, most robustly in those with less severe repetitive behaviors and better starting balance. The training was perceived as motivating, further suggesting its efficacy and likelihood of use.

Longitudinal development of thalamic and internal capsule microstructure in autism spectrum disorder.

The thalamus is a key sensorimotor relay area that is implicated in autism spectrum disorder (ASD). However, it is unknown how the thalamus and white-matter structures that contain thalamo-cortical fiber connections (e.g., the internal capsule) develop from childhood into adulthood and whether this microstructure relates to basic motor challenges in ASD. We used diffusion weighted imaging in a cohort-sequential design to assess longitudinal development of the thalamus, and posterior- and anterior-limbs of the internal capsule (PLIC and ALIC, respectively) in 89 males with ASD and 56 males with typical development (3-41 years; all verbal). Our results showed that the group with ASD exhibited different developmental trajectories of microstructure in all regions, demonstrating childhood group differences that appeared to approach and, in some cases, surpass the typically developing group in adolescence and adulthood. The PLIC (but not ALIC nor thalamus) mediated the relation between age and finger-tapping speed in both groups. Yet, the gap in finger-tapping speed appeared to widen at the same time that the between-group gap in the PLIC appeared to narrow. Overall, these results suggest that childhood group differences in microstructure of the thalamus and PLIC become less robust in adolescence and adulthood. Further, finger-tapping speed appears to be mediated by the PLIC in both groups, but group differences in motor speed that widen during adolescence and adulthood suggest that factors beyond the microstructure of the thalamus and internal capsule may contribute to atypical motor profiles in ASD. Autism Res 2018, 11: 450-462. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Microstructure of the thalamus, a key sensory and motor brain area, appears to develop differently in individuals with autism spectrum disorder (ASD). Microstructure is important because it informs us of the density and organization of different brain tissues. During childhood, thalamic microstructure was distinct in the ASD group compared to the typically developing group. However, these group differences appeared to narrow with age, suggesting that the thalamus continues to dynamically change in ASD into adulthood.

Impaired mTORC2 signaling in catecholaminergic neurons exaggerates high fat diet-induced hyperphagia.

OBJECTIVE: Food intake is highly regulated by central homeostatic and hedonic mechanisms in response to peripheral and environmental cues. Neutral energy balance stems from proper integration of homeostatic signals with those "sensing" the rewarding properties of food. Impairments in brain insulin signaling causes dysregulation of feeding behaviors and, as a consequence, hyperphagia. Here, we sought to determine how the mammalian target of rapamycin complex 2 (mTORC2), a complex involved in insulin signaling, influences high fat feeding. METHODS: Rictor is a subunit of mTORC2, and its genetic deletion impairs mTORC2 activity. We used Cre-LoxP technology to delete Rictorin tyrosine hydroxylase (TH) expressing neurons (TH Rictor KO). We assessed food intake, body weight, body composition and DA dependent behaviors. RESULTS: TH Rictor KO mice display a high-fat diet specific hyperphagia, yet, when on low-fat diet, their food intake is indistinguishable from controls. Consistently, TH Rictor KO become obese only while consuming high-fat diet. This is paralleled by reduced brain DA content, and disruption of DA dependent behaviors including increased novelty-induced hyperactivity and exaggerated response to the psycho stimulant amphetamine (AMPH). CONCLUSIONS: Our data support a model in which mTORC2 signaling within catecholaminergic neurons constrains consumption of a high-fat diet, while disruption causes high-fat diet-specific exaggerated hyperphagia. In parallel, impaired mTORC2 signaling leads to aberrant striatal DA neurotransmission, which has been associated with obesity in human and animal models, as well as with escalating substance abuse. These data suggest that defects localized to the catecholaminergic pathways are capable of overriding homeostatic circuits, leading to obesity, metabolic impairment, and aberrant DA-dependent behaviors.