Cannabinoid CB1 Receptor Deletion from Catecholaminergic Neurons Protects from Diet-Induced Obesity.

High-calorie diets and chronic stress are major contributors to the development of obesity and metabolic disorders. These two risk factors regulate the activity of the sympathetic nervous system (SNS). The present study showed a key role of the cannabinoid type 1 receptor (CB1) in dopamine ß-hydroxylase (dbh)-expressing cells in the regulation of SNS activity. In a diet-induced obesity model, CB1 deletion from these cells protected mice from diet-induced weight gain by increasing sympathetic drive, resulting in reduced adipogenesis in white adipose tissue and enhanced thermogenesis in brown adipose tissue. The deletion of CB1 from catecholaminergic neurons increased the plasma norepinephrine levels, norepinephrine turnover, and sympathetic activity in the visceral fat, which coincided with lowered neuropeptide Y (NPY) levels in the visceral fat of the mutant mice compared with the controls. Furthermore, the mutant mice showed decreased plasma corticosterone levels. Our study provided new insight into the mechanisms underlying the roles of the endocannabinoid system in regulating energy balance, where the CB1 deletion in dbh-positive cells protected from diet-induced weight gain via multiple mechanisms, such as increased SNS activity, reduced NPY activity, and decreased basal hypothalamic-pituitary-adrenal (HPA) axis activity.

Cell type specific impact of cannabinoid receptor signaling in somatosensory barrel map formation in mice.

Endocannabinoids and their receptors are highly abundant in the developing cerebral cortex and play major roles in early developmental processes, for example, neuronal proliferation, migration, and axonal guidance as well as postnatal plasticity. To investigate the role of the cannabinoid type 1 receptor (CB1) in the formation of sensory maps in the cerebral cortex, the topographic representation of the whiskers in the primary somatosensory cortex (barrel field) of adult mice with different cell type specific genetic deletion of CB1 was studied. A constitutive absence of CB1 (CB1-KO) significantly decreased the total area of the somatosensory cortical map, affecting barrel, and septal areas. Cell specific CB1 deletion in dorsal telencephalic glutamatergic neurons only (Glu-CB1-KO) or in both glutamatergic and forebrain GABAergic neurons (Glu/GABA-CB1-KO) resulted in an increased septa area in the barrel field map. No significant modifications in area parameters could be observed in GABA-CB1-KO mice. These data demonstrate that CB1 signaling especially in cortical glutamatergic neurons is essential for the development of topographic maps in the cerebral cortex.

Gadd45α modulates aversive learning through post-transcriptional regulation of memory-related mRNAs.

Learning is essential for survival and is controlled by complex molecular mechanisms including regulation of newly synthesized mRNAs that are required to modify synaptic functions. Despite the well-known role of RNA-binding proteins (RBPs) in mRNA functionality, their detailed regulation during memory consolidation is poorly understood. This study focuses on the brain function of the RBP Gadd45α (growth arrest and DNA damage-inducible protein 45 alpha, encoded by the Gadd45a gene). Here, we find that hippocampal memory and long-term potentiation are strongly impaired in Gadd45a-deficient mice, a phenotype accompanied by reduced levels of memory-related mRNAs. The majority of the Gadd45α-regulated transcripts show unusually long 3' untranslated regions (3'UTRs) that are destabilized in Gadd45a-deficient mice via a transcription-independent mechanism, leading to reduced levels of the corresponding proteins in synaptosomes. Moreover, Gadd45α can bind specifically to these memory-related mRNAs. Our study reveals a new function for extended 3'UTRs in memory consolidation and identifies Gadd45α as a novel regulator of mRNA stability.

Cannabinoid Receptor Type 1 in the Brain Regulates the Affective Component of Visceral Pain in Mice.

Endocannabinoids acting through cannabinoid receptor type 1 (CB1) are major modulators of peripheral somatic and visceral nociception. Although only partially studied, some evidence suggests a particular role of CB1 within the brain in nociceptive processes. As the endocannabinoid system regulates affect and emotional behaviors, we hypothesized that cerebral CB1 influences affective processing of visceral pain-related behaviors in laboratory animals. To study nocifensive responses modulated by supraspinal CB1, we used conditional knock-out mice lacking CB1 either in cortical glutamatergic neurons (Glu-CB1-KO), or in forebrain GABAergic neurons (GABA-CB1-KO), or in principal neurons of the forebrain (CaMK-CB1-KO). These mutant mice and mice treated with the CB1 antagonist SR141716 were tested for different pain-related behaviors. In an acetic acid-induced abdominal constriction test, supraspinal CB1 deletions did not affect nocifensive responses. In the cerulein-model of acute pancreatitis, mechanical allodynia or hyperalgesia were not changed, but Glu-CB1- and CaMK-CB1-KO mice showed significantly increased facial grimacing scores indicating increased affective responses to this noxious visceral stimulus. Similarly, these brain-specific CB1 KO mice also showed significantly changed thermal nociception in a hot-plate test. These results reveal a novel, and important role of CB1 expressed by cortical glutamatergic neurons in the affective component of visceral nociception.

Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages.

Dysregulated adipocyte physiology leads to imbalanced energy storage, obesity, and associated diseases, imposing a costly burden on current health care. Cannabinoid receptor type-1 (CB1) plays a crucial role in controlling energy metabolism through central and peripheral mechanisms. In this work, adipocyte-specific inducible deletion of the CB1 gene (Ati-CB1-KO) was sufficient to protect adult mice from diet-induced obesity and associated metabolic alterations and to reverse the phenotype in already obese mice. Compared with controls, Ati-CB1-KO mice showed decreased body weight, reduced total adiposity, improved insulin sensitivity, enhanced energy expenditure, and fat depot-specific cellular remodeling toward lowered energy storage capacity and browning of white adipocytes. These changes were associated with an increase in alternatively activated macrophages concomitant with enhanced sympathetic tone in adipose tissue. Remarkably, these alterations preceded the appearance of differences in body weight, highlighting the causal relation between the loss of CB1 and the triggering of metabolic reprogramming in adipose tissues. Finally, the lean phenotype of Ati-CB1-KO mice and the increase in alternatively activated macrophages in adipose tissue were also present at thermoneutral conditions. Our data provide compelling evidence for a crosstalk among adipocytes, immune cells, and the sympathetic nervous system (SNS), wherein CB1 plays a key regulatory role.

What explains functioning from the perspective of people with multiple sclerosis?

The Brief International Classification of Functioning, Disability and Health (ICF) Core Set for MS was developed to capture functioning in people with multiple sclerosis (pwMS). This study examined whether categories in the Brief ICF Core Set for MS best capture different levels of functioning in pwMS. We used data of a multicenter cross-sectional study collected from 205 pwMS using the ICF categories of the MS-specific WHO ICF Checklist and the individual rating of functioning. ICF categories to be entered in an initial regression model were selected following a systematic procedure in accordance with the ICF structure. Based on the initial regression model using stepwise Ordinary Least-Squares regression analyses, additional models were designed by substituting the ICF categories in final model. The selected set of categories was compared with the Brief ICF Core Set for MS. Eleven ICF categories were identified that best differentiate among different levels of functioning. Four were part of the Brief ICF Core Set. ICF categories identified in this study may be used as outcome measures in further study, parameters to monitor functioning along the continuum of health care and lifespan, and to define different subgroups of pwMS.

Content validity of the Comprehensive ICF Core Set for multiple sclerosis from the perspective of speech and language therapists.

BACKGROUND: The Comprehensive International Classification of Functioning, Disability and Health (ICF) Core Set for Multiple Sclerosis (MS) is a comprehensive framework to structure the information obtained in multidisciplinary clinical settings according to the biopsychosocial perspective of the International Classification of Functioning, Disability and Health (ICF) and to guide the treatment and rehabilitation process accordingly. It is now undergoing validation from the user perspective for which it has been developed in the first place. AIMS: To validate the content of the Comprehensive ICF Core Set for MS from the perspective of speech and language therapists (SLTs) involved in the treatment of persons with MS (PwMS). METHODS & PROCEDURES: Within a three-round e-mail-based Delphi Study 34 SLTs were asked about PwMS' problems, resources and aspects of the environment treated by SLTs. Responses were linked to ICF categories. Identified ICF categories were compared with those included in the Comprehensive ICF Core Set for MS to examine its content validity. OUTCOMES & RESULTS: Thirty-four SLTs named 524 problems and resources, as well as aspects of environment. Statements were linked to 129 ICF categories (60 Body-functions categories, two Body-structures categories, 42 Activities-&-participation categories, and 25 Environmental-factors categories). SLTs confirmed 46 categories in the Comprehensive ICF Core Set. Twenty-one ICF categories were identified as not-yet-included categories. CONCLUSIONS & IMPLICATIONS: This study contributes to the content validity of the Comprehensive ICF Core Set for MS from the perspective of SLTs. Study participants agreed on a few not-yet-included categories that should be further discussed for inclusion in a revised version of the Comprehensive ICF Core Set to strengthen SLTs' perspective in PwMS' neurorehabilitation.

Pre- and postsynaptic type-1 cannabinoid receptors control the alterations of glutamate transmission in experimental autoimmune encephalomyelitis.

Type-1 cannabinoid receptors (CB1R) are important regulators of the neurodegenerative damage in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). In GABAergic striatal neurons, CB1R stimulation exerts protective effects by limiting inflammation-induced potentiation of glutamate-mediated spontaneous excitatory postsynaptic currents (sEPSCs). Here we show that CB1R located on GABAergic or on glutamatergic neurons are differentially involved in the pre- and postsynaptic alterations of sEPSCs caused by EAE in the striatum. After induction of EAE, mice selectively lacking CB1R on GABAergic neurons (GABA-CB1R-KO) showed exacerbated alterations of sEPSC duration in GABAergic medium spiny neurons (MSN). On the other hand, EAE-induced alterations of corticostriatal sEPSC frequency were exacerbated only in mice lacking CB1R on glutamatergic neurons (Glu-CB1R-KO), indicating that this subset of receptors controls the effects of inflammation on glutamate release. While EAE severity was enhanced in whole CB1R-KO mice, GABA-CB1R-KO and Glu-CB1R-KO mice had similar motor deficits as the respective wild-type (WT) counterparts. Our results provide further evidence that CB1R are involved in EAE pathophysiology, and suggest that both pre- and postsynaptic alterations of glutamate transmission are important to drive excitotoxic neurodegeneration typical of this disorder.

Cannabinoid receptor 1 deficiency in a mouse model of Alzheimer's disease leads to enhanced cognitive impairment despite of a reduction in amyloid deposition.

Alzheimer's disease (AD) is characterized by amyloid-ß deposition in amyloid plaques, neurofibrillary tangles, inflammation, neuronal loss, and cognitive deficits. Cannabinoids display neuromodulatory and neuroprotective effects and affect memory acquisition. Here, we studied the impact of cannabinoid receptor type 1 (CB1) deficiency on the development of AD pathology by breeding amyloid precursor protein (APP) Swedish mutant mice (APP23), an AD animal model, with CB1-deficient mice. In addition to the lower body weight of APP23/CB1(-/-) mice, most of these mice died at an age before typical AD-associated changes become apparent. The surviving mice showed a reduced amount of APP and its fragments suggesting a regulatory influence of CB1 on APP processing, which was confirmed by modulating CB1 expression in vitro. Reduced APP levels were accompanied by a reduced plaque load and less inflammation in APP23/CB1(-/-) mice. Nevertheless, compared to APP23 mice with an intact CB1, APP23/CB1(-/-) mice showed impaired learning and memory deficits. These data argue against a direct correlation of amyloid plaque load with cognitive abilities in this AD mouse model lacking CB1. Furthermore, the findings indicate that CB1 deficiency can worsen AD-related cognitive deficits and support a potential role of CB1 as a pharmacologic target.

Validation of the comprehensive ICF core set for multiple sclerosis from the perspective of physical therapists.

BACKGROUND: The Comprehensive ICF Core Set for Multiple Sclerosis (MS) is an application of the International Classification of Functioning, Disability and Health (ICF) and represents the typical spectrum of problems in the functioning of people with MS. OBJECTIVES: The objective of this study was to validate the Comprehensive ICF Core Set for MS from the perspective of physical therapists. DESIGN: A 3-round survey based on the Delphi technique was used. METHODS: Physical therapists experienced in the management of MS were asked about problems and resources of people with MS as well as environmental aspects treated by physical therapists (eg, use of assistive devices, support). Statements were linked to the ICF and compared with the Comprehensive ICF Core Set for MS. RESULTS: Eighty physical therapists from 23 countries mentioned 2,133 issues that covered all of the ICF components. Two hundred thirty-eight ICF categories were linked to the statements. Forty-six categories in the Comprehensive ICF Core Set for MS were confirmed by physical therapists at the same level or a more specific level of classification. Nineteen additional ICF categories were reported by at least 75% of the participants. CONCLUSIONS: The results of this study support the content and face validity of the Comprehensive ICF Core Set for MS. Areas of functioning and health that physical therapists believe should be assessed were identified. The findings of this study as well as the results of completed and ongoing validation studies will further elucidate the validity of the Comprehensive ICF Core Set for MS from different perspectives.

Validation of the comprehensive ICF core set for multiple sclerosis from the perspective of occupational therapists.

OBJECTIVE: The comprehensive ICF core set for multiple sclerosis (MS) is an application of the international classification of functioning, disability and health (ICF) and represents the typical spectrum of problems in functioning of people with MS (PwMS). The objective of this study was to validate this ICF core set from the perspective of occupational therapists (OTs). METHOD: In a three-round Delphi study, OTs were asked about problems and resources of PwMS, as well as environmental aspects treated by OTs. Statements were linked to the ICF and compared with the categories included in the comprehensive ICF core set for MS. RESULTS: Sixty-one OTs from 21 countries agreed on 71 categories that are included in the comprehensive ICF core set for MS (19 body functions, 40 categories of activities and participation, 12 environmental factors). Eleven ICF categories were identified as not-yet-included ICF categories in the comprehensive ICF core set for MS (6 body functions, 2 categories of Activities and participation, 3 environmental factors). CONCLUSION: This study contributes to the validity of the ICF categories included in the comprehensive ICF core set. It outlines which areas of functioning and health are relevant for PwMS from the perspective of OTs and consequently should be assessed.