Cannabidiol Exposure During the Mouse Adolescent Period Is Without Harmful Behavioral Effects on Locomotor Activity, Anxiety, and Spatial Memory

Cannabidiol (CBD) is a non-intoxicating phytocannabinoid whose purported therapeutic benefits and impression of a high safety profile has promoted its increasing popularity. CBD’s popularity is also increasing among children and adolescents who are being administered CBD, off label, for the treatment of numerous symptoms associated with autism spectrum disorder, attention deficit hyperactivity disorder, anxiety, and depression. The relative recency of its use in the adolescent population has precluded investigation of its impact on the developing brain and the potential consequences that may present in adulthood. Therefore, there’s an urgency to identify whether prolonged adolescent CBD exposure has substantive impacts on the developing brain that impact behavioral and cognitive processes in adulthood. Here, we tested the effect of twice-daily intraperitoneal administrations of CBD (20 mg/kg) in male and female C57BL/6J mice during the adolescent period of 25–45 days on weight gain, and assays for locomotor behavior, anxiety, and spatial memory. Prolonged adolescent CBD exposure had no detrimental effects on locomotor activity in the open field, anxiety behavior on the elevated plus maze, or spatial memory in the Barnes Maze compared to vehicle-treated mice. Interestingly, CBD-treated mice had a faster rate of learning in the Barnes Maze. However, CBD-treated females had reduced weight gain during the exposure period. We conclude that prolonged adolescent CBD exposure in mice does not have substantive negative impacts on a range of behaviors in adulthood, may improve the rate of learning under certain conditions, and impacts weight gain in a sex-specific manner.

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A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin β-cluster genes in the developing brain

Molecular Psychiatry ◽

10.1038/s41380-021-01199-7 ◽

2021 ◽

Author(s):

Shabeesh Balan ◽

Yoshimi Iwayama ◽

Tetsuo Ohnishi ◽

Mikiko Fukuda ◽

Atsuko Shirai ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Autism Spectrum ◽

Developing Brain ◽

Spectrum Disorder ◽

Loss Of Function ◽

H3k9 Trimethylation

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Abstract 19727: ROCK2 Mediates Browning of White Fat and Protects Against Obesity

Circulation ◽

10.1161/circ.130.suppl_2.19727 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Phetcharat Chen ◽

Christina Park ◽

Eltayeb Karrar ◽

Chaoyung Wang ◽

James Liao

Keyword(s):

Weight Gain ◽

Body Temperature ◽

Cold Exposure ◽

Diet Induced Obesity ◽

Therapeutic Benefits ◽

White Adipocytes ◽

Important Regulator ◽

And Function ◽

White Fat ◽

Adipocyte Development

Background: The Rho-activated kinases (ROCK1 and ROCK2) are serine threonine kinases that are ubiquitously expressed with higher levels of ROCK2 compared to ROCK1 in adipocytes. Recent studies suggest that ROCK2 may be an important regulator of energy metabolism and obesity. However, its role in adipocyte development and function is unknown. Methods and Result: To determine the role of ROCK2 in adipocyte development and obesity, we generated adipocyte-specific deletion (ROCK2 adipoQ-/- ) and overexpression (CA-ROCK adipoQ+/+ ) of ROCK2 in mice. Compared to control mice, CA-ROCK adipoQ+/+ mice exhibited increased browning of inguinal white adipose tissue (iWAT). Indeed, immunohistochemical staining of iWAT in CA-ROCK adipoQ+/+ mice showed that UCP1 was upregulated. Furthermore, CA-ROCK adipoQ+/+ mice on high fat diet were resistant to weight gain and obesity for up to 18 weeks. This is in contrast to ROCK2 adipoQ-/- mice, which developed more weight gain or obesity than control mice. To determine the physiological effects of ROCK2 on browning of iWAT, control and ROCK2 adipoQ-/- mice were exposed to 4°C for 1 week. In control mice, cold exposure increased ROCK2 activity and lead to browning of iWAT. However, the iWAT in ROCK2 adipoQ-/- mice failed to undergo browning. Analysis of gene expression in iWAT demonstrated increased UCP1 and mitochondria proteins in control but not ROCK2 adipoQ-/- mice. Thermal imaging revealed that ROCK2 adipoQ-/- mice were unable to maintain basal body temperature after prolonged cold exposure. In contrast, the heat map of the CA-ROCK adipoQ+/+ mice showed an elevation of body temperature, particularly in areas of iWAT as compared to that of control littermates. Conclusions: ROCK2 mediates the “browning” of white adipocytes and prevents the development of obesity through increased thermogenesis. These findings suggest that the activation of ROCK2 in adipocytes may have therapeutic benefits in preventing diet-induced obesity.

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Regional differences in Alzheimer’s disease pathology confound behavioural rescue after amyloid-β attenuation

Brain ◽

10.1093/brain/awz371 ◽

2019 ◽

Vol 143 (1) ◽

pp. 359-373 ◽

Cited By ~ 5

Author(s):

Christopher D Morrone ◽

Paolo Bazzigaluppi ◽

Tina L Beckett ◽

Mary E Hill ◽

Margaret M Koletar ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Cognitive Function ◽

Spatial Memory ◽

Regional Differences ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Barnes Maze ◽

Tau Pathology

Abstract Failure of Alzheimer’s disease clinical trials to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. To dissect contributions of individual pathologies to cognitive function, we used the TgF344-AD rat model, which recapitulates the salient hallmarks of Alzheimer’s disease pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). scyllo-Inositol treatment attenuated amyloid-β peptide in disease-bearing TgF344-AD rats, which rescued pattern separation in the novel object recognition task and executive function in the reversal learning phase of the Barnes maze. Interestingly, neither activities of daily living in the burrowing task nor spatial memory in the Barnes maze were rescued by attenuating amyloid-β peptide. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and in vivo electrophysiological signature of the hippocampus. Amyloid-β peptide attenuation reduced hippocampal tau pathology and rescued adult hippocampal neurogenesis and neuronal function, via improvements in cross-frequency coupling between theta and gamma bands. To investigate mechanisms underlying the persistence of spatial memory deficits, we next examined neuropathology in the entorhinal cortex, a region whose input to the hippocampus is required for spatial memory. Reduction of amyloid-β peptide in the entorhinal cortex had no effect on entorhinal tau pathology or entorhinal-hippocampal neuronal network dysfunction, as measured by an impairment in hippocampal response to entorhinal stimulation. Thus, rescue or not of cognitive function is dependent on regional differences of amyloid-β, tau and neuronal network dysfunction, demonstrating the importance of staging disease in patients prior to enrolment in clinical trials. These results further emphasize the need for combination therapeutic approaches across disease progression.

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Social Interaction Improved by Oxytocin in the Subclass of Autism with Comorbid Intellectual Disabilities

Diseases ◽

10.3390/diseases7010024 ◽

2019 ◽

Vol 7 (1) ◽

pp. 24 ◽

Cited By ~ 10

Author(s):

Haruhiro Higashida ◽

Toshio Munesue ◽

Hirotaka Kosaka ◽

Hidenori Yamasue ◽

Shigeru Yokoyama ◽

...

Keyword(s):

Social Interaction ◽

Adverse Effects ◽

Intellectual Disabilities ◽

Autism Spectrum ◽

Pilot Studies ◽

Therapeutic Benefits ◽

Adolescents And Adults ◽

History Of ◽

History Of Epilepsy ◽

Adults With Asd

Approximately half of all autism spectrum disorder (ASD) individuals suffer from comorbid intellectual disabilities. Furthermore, the prevalence of epilepsy has been estimated to be 46% of patients with low intelligence quotient. It is important to investigate the therapeutic benefits and adverse effects of any recently developed drugs for this proportion of individuals with the so-called Kanner type of ASD. Therefore, we investigated the therapeutic and/or adverse effects of intranasal oxytocin (OT) administration, especially in adolescents and adults with ASD and comorbid intellectual disability and epilepsy, with regard to core symptoms of social deficits. We have already reported three randomized placebo-controlled trials (RCTs). However, we revisit results in our pilot studies from the view of comorbidity. Most of the intellectually disabled participants were found to be feasible participants of the RCT. We observed significantly more events regarded as reciprocal social interaction in the OT group compared with the placebo group. In the trial, no or little differences in adverse events were found between the OT and placebo arms, as found in some other reports. However, seizures were induced in three participants with medical history of epilepsy during or after OT treatment. In conclusion, we stress that behavioral changes in ASD patients with intellectual disabilities could be recognized not by the conventional measurements of ASD symptoms but by detailed evaluation of social interactions arising in daily-life situations.

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Allocentric Versus Egocentric Spatial Memory in Adults with Autism Spectrum Disorder

Journal of Autism and Developmental Disorders ◽

10.1007/s10803-018-3465-5 ◽

2018 ◽

Vol 48 (6) ◽

pp. 2101-2111 ◽

Cited By ~ 9

Author(s):

Melanie Ring ◽

Sebastian B. Gaigg ◽

Mareike Altgassen ◽

Peter Barr ◽

Dermot M. Bowler

Keyword(s):

Autism Spectrum Disorder ◽

Spatial Memory ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Adults With Autism

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Risk Factors for Unhealthy Weight Gain and Obesity among Children with Autism Spectrum Disorder

International Journal of Molecular Sciences ◽

10.3390/ijms20133285 ◽

2019 ◽

Vol 20 (13) ◽

pp. 3285 ◽

Cited By ~ 9

Author(s):

Khushmol K. Dhaliwal ◽

Camila E. Orsso ◽

Caroline Richard ◽

Andrea M. Haqq ◽

Lonnie Zwaigenbaum

Keyword(s):

Risk Factors ◽

Autism Spectrum Disorder ◽

Weight Gain ◽

Autism Spectrum ◽

Lifestyle Factors ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Future Research ◽

Children With Asd ◽

Unhealthy Weight

Autism Spectrum Disorder (ASD) is a developmental disorder characterized by social and communication deficits and repetitive behaviors. Children with ASD are also at a higher risk for developing overweight or obesity than children with typical development (TD). Childhood obesity has been associated with adverse health outcomes, including insulin resistance, diabetes, heart disease, and certain cancers. Importantly some key factors that play a mediating role in these higher rates of obesity include lifestyle factors and biological influences, as well as secondary comorbidities and medications. This review summarizes current knowledge about behavioral and lifestyle factors that could contribute to unhealthy weight gain in children with ASD, as well as the current state of knowledge of emerging risk factors such as the possible influence of sleep problems, the gut microbiome, endocrine influences and maternal metabolic disorders. We also discuss some of the clinical implications of these risk factors and areas for future research.

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A238 ABSENCE OF AGE-RELATED MEMORY DECLINE IN GERM-FREE MICE

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwab002.236 ◽

2021 ◽

Vol 4 (Supplement_1) ◽

pp. 288-289

Author(s):

N Kraimi ◽

G De Palma ◽

J Lu ◽

D Bowdish ◽

E Verdu ◽

...

Keyword(s):

Locomotor Activity ◽

Spatial Memory ◽

Cognitive Decline ◽

Memory Performance ◽

Alternation Rate ◽

Memory Decline ◽

Germ Free ◽

Age Related ◽

Old Mice ◽

Young Mice

Abstract Background Age-associated deterioration of cognitive function and memory capacity occur in a variety of mammals, from humans to rodents. For example, significant memory deficits have been reported in conventionally raised (SPF) old mice compared to conventionally raised young mice submitted to a spatial memory task (Prevot et al., Mol Neuropsychiatry 2019). Microbiota to brain signaling is now well established in mice, but the extent to which this influences age-related memory decline is unknown. Aims Our project aims to determine whether the intestinal microbiota contributes to age-related changes in brain function. We address the hypothesis that age-related cognitive decline is attenuated in the absence of the intestinal microbiota. Methods We studied locomotor behavior and spatial memory performance in young germ-free (GF) mice (2–3 months of age, n=24) and senescent GF mice (13–27 months old, n=22) maintained in axenic conditions, and compared them to conventionally raised (SPF) mice. We used the Y-maze test based on a spontaneous alternations task to assess cognition, with alternation rate as a proxy of spatial working memory performance. The locomotor activity was measured using the open-field test. Results GF old mice traveled less distance (458.9 cm) than GF young mice (875.7 cm, p < 0.001) but these differences in locomotor activity did not influence spatial memory performance. Indeed, both GF old and GF young mice had an identical alternation rate of 73.3% (p > 0.05). This contrasted with the memory impairment found in old SPF mice that displayed lower alternation rate of 58.3%, compared to that found in young SPF mice (76.2%, p = 0.13). Conclusions We conclude that the absence of age-related memory decline in germ-free mice is consistent with a role for the microbiota in the cognitive decline associated with aging, likely through action on the immune system, well documented in SPF mice (Thevaranjan et al., Cell Host & Microbe 2017). We propose that novel microbiota-targeted therapeutic strategies may delay or prevent the cognitive decline of aging. Funding Agencies CIHRBalsam Family Foundation

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Different effects of Bifeprunox, Aripiprazole, and Haloperidol on body weight gain, food and water intake, and locomotor activity in rats

Pharmacology Biochemistry and Behavior ◽

10.1016/j.pbb.2014.06.004 ◽

2014 ◽

Vol 124 ◽

pp. 167-173 ◽

Cited By ~ 11

Author(s):

Michael De Santis ◽

Bo Pan ◽

Jiamei Lian ◽

Xu-Feng Huang ◽

Chao Deng

Keyword(s):

Body Weight ◽

Weight Gain ◽

Locomotor Activity ◽

Water Intake ◽

Body Weight Gain ◽

Food And Water Intake

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Development of obesity in transgenic rats with low circulating growth hormone levels: involvement of leptin resistance

Acta Endocrinologica ◽

10.1530/eje.0.1430535 ◽

2000 ◽

pp. 535-541 ◽

Cited By ~ 31

Author(s):

Y Furuhata ◽

R Kagaya ◽

K Hirabayashi ◽

A Ikeda ◽

KT Chang ◽

...

Keyword(s):

Growth Hormone ◽

Cerebrospinal Fluid ◽

Body Weight ◽

Weight Gain ◽

Locomotor Activity ◽

Food Intake ◽

Body Weight Gain ◽

Leptin Resistance ◽

Intracerebroventricular Injection ◽

Transgenic Rats

BACKGROUND: Human growth hormone (hGH) transgenic (TG) rats have been produced in our laboratory. These TG rats are characterized by low circulating hGH levels, virtually no endogenous rGH secretion, and massive obesity. OBJECTIVE: To elucidate how energy balance and leptin sensitivity contributed to the establishment of this obesity. DESIGN AND METHODS: Food intake, locomotor activity and leptin concentrations in serum and cerebrospinal fluid were measured in TG rats and their non-transgenic littermates (control). The effect of intraperitoneal and intracerebroventricular injection of leptin on food intake and body weight gain was also examined. RESULTS: An increase in food intake and a decrease in locomotor activity were observed from 4 and 7 weeks of age, respectively, in the transgenic rats compared with control. Serum leptin concentrations of the transgenic rats were more than twice as high as those of control rats and were associated with an increased white adipose tissue mass and ob gene expression. Intraperitoneal injection of leptin significantly decreased food intake and body weight gain in control rats, but not in transgenic rats. Leptin concentration in the cerebrospinal fluid of transgenic rats was not different from that of control rats, and intracerebroventricular injection of leptin was similarly effective in reducing food intake and body weight gain as it was in control rats. CONCLUSIONS: These results suggest that the transgenic rats, whose GH secretion is suppressed, develop obesity due to early onset of an increase in food intake and a decrease in locomotor activity with leptin resistance resulting from deteriorating leptin transport from peripheral blood to cerebrospinal fluid.

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