PP2B-Dependent Cerebellar Plasticity Sets the Amplitude of the Vestibulo-ocular Reflex during Juvenile Development.

Throughout life, the cerebellum plays a central role in the coordination and optimization of movements, using cellular plasticity to adapt a range of behaviors. Whether these plasticity processes establish a fixed setpoint during development, or continuously adjust behaviors throughout life, is currently unclear. Here, by spatiotemporally manipulating the activity of protein phosphatase 2B (PP2B), an enzyme critical for cerebellar plasticity in male and female mice, we examined the consequences of disrupted plasticity on the performance and adaptation of the vestibulo-ocular reflex (VOR). We find that, in contrast to Purkinje cell (PC)-specific deletion starting early postnatally, acute pharmacological as well as adult-onset genetic deletion of PP2B affects all forms of VOR adaptation but not the level of VOR itself. Next, we show that PC-specific genetic deletion of PP2B in juvenile mice leads to a progressive loss of the protein PP2B and a concurrent change in the VOR, in addition to the loss of adaptive abilities. Finally, re-expressing PP2B in adult mice that lack PP2B expression from early development rescues VOR adaptation but does not affect the performance of the reflex. Together, our results indicate that chronic or acute, genetic, or pharmacological block of PP2B disrupts the adaptation of the VOR. In contrast, only the absence of plasticity during cerebellar development affects the setpoint of VOR, an effect that cannot be corrected after maturation of the cerebellum. These findings suggest that PP2B-dependent cerebellar plasticity is required during a specific period to achieve the correct setpoint of the VOR.

Pre-ataxic loss of intrinsic plasticity and motor learning in a mouse model of SCA1.

Spinocerebellar ataxias are neurodegenerative diseases, the hallmark symptom of which is the development of ataxia due to cerebellar dysfunction. Purkinje cells, the principal neurons of the cerebellar cortex, are the main cells affected in these disorders, but the sequence of pathological events leading to their dysfunction is poorly understood. Understanding the origins of Purkinje cells dysfunction before it manifests is imperative to interpret the functional and behavioural consequences of cerebellar-related disorders, providing an optimal timeline for therapeutic interventions. Here, we report the cascade of events leading to Purkinje cells dysfunction before the onset of ataxia in a mouse model of spinocerebellar ataxia 1 (SCA1). Spatiotemporal characterization of the ATXN1[82Q] SCA1 mouse model revealed high levels of the mutant ATXN1[82Q] weeks before the onset of ataxia. The expression of the toxic protein first caused a reduction of Purkinje cells intrinsic excitability, which was followed by atrophy of Purkinje cells dendrite arborization and aberrant glutamatergic signalling, finally leading to disruption of Purkinje cells innervation of climbing fibres and loss of intrinsic plasticity of Purkinje cells. Functionally, we found that deficits in eyeblink conditioning, a form of cerebellum-dependent motor learning, precede the onset of ataxia, matching the timeline of climbing fibre degeneration and reduced intrinsic plasticity. Together, our results suggest that abnormal synaptic signalling and intrinsic plasticity during the pre-ataxia stage of spinocerebellar ataxias underlie an aberrant cerebellar circuitry that anticipates the full extent of the disease severity. Furthermore, our work indicates the potential for eyeblink conditioning to be used as a sensitive tool to detect early cerebellar dysfunction as a sign of future disease.

Talking About Sexuality With Youth: A Taboo in Psychiatry?

BACKGROUND: Young people who have psychiatric problems are more likely than their peers to endure difficulties during their sexual and gender identity development. AIM: This study aims to examine the communication between mental health care providers and their patients about the topics of relations, sexuality and gender identity, including a description of professionals' attitudes toward these topics and the factors that contribute to and inhibit communication. METHODS: Study participants (n = 242, response rate = 31%) were a representative sample of a large multicenter cohort of 768 mental health care professionals (eg, medical doctors, psychiatrists, psychologists, group counselors, parent counselors) of 7 institutions and 5 solo practices in the Netherlands, who completed a survey on communication about sexuality and gender identity with their young patients (age 12-21 years). OUTCOMES: Sexuality and gender identity are infrequently discussed by mental health care providers with their young patients or their patients' parents. RESULTS: Of the study sample, 99.5 % valued sexuality as an important topic to discuss with their patients. However, only 17.1% of the professionals reported that they discussed sexuality-related issues with the majority (>75%) of their patients (adolescents: 19.9%, parents: 14.4%) Additionally, only 2.3 % of the participants discussed gender nonconformity regularly with patients. Information about sexual side effects of prescribed medication was infrequently (20.3%) provided: antidepressants (40.0%), antipsychotics (34.0%), benzodiazepines (5.1%) and stimulants (2.4%). The most frequently cited reasons for not discussing these topics were a lack of awareness, own feelings of discomfort, and the patients' supposed feelings of shame. There was no gender differences observed. CLINICAL IMPLICATIONS: Recommendations for professionals include to be aware of these topics, initiating age-appropriate conversation and use inclusive language. STRENGTHS AND LIMITATIONS: The present study included a diverse and representative group of mental health care professionals. Frequency of sexual communication was based on self-report, which brings a risk of bias. CONCLUSION: Despite a recognized need to engage in age-appropriate communication about sexuality and gender identity in youth mental health care, mental health providers seem to remain hesitant to discuss such topics. Bungener SL, Post L, Berends I, et al. Talking About Sexuality With Youth: A Taboo in Psychiatry?. J Sex Med 2022;19:421-429.

Mechanisms underlying vestibulo-cerebellar motor learning in mice depend on movement direction.

KEY POINTS: Directionality, inherent to movements, has behavioural and neuronal correlates. Direction of vestibular stimulation determines motor learning efficiency. Vestibulo-ocular reflex gain-increase correlates with Purkinje cell simple spike potentiation. The locus of neural correlates for vestibulo-ocular reflex adaptation is paradigm specific. ABSTRACT: Compensatory eye movements elicited by head rotation, also known as vestibulo-ocular reflex (VOR), can be adapted with the use of visual feedback. The cerebellum is essential for this type of movement adaptation, although its neuronal correlates remain to be clarified. In the present study, we show that the direction of vestibular input determines the magnitude of eye movement adaptation induced by mismatched visual input in mice, with larger changes during contraversive head rotation. Moreover, the location of the neural correlate of this changed behaviour depends on the type of paradigm. Gain-increase paradigms induce increased simple spike (SS) activity in ipsilateral cerebellar Purkinje cells (PC), which is in line with eye movements triggered by optogenetic PC activation. By contrast, gain-decrease paradigms do not induce changes in SS activity, indicating that the murine vestibulo-cerebellar cortical circuitry is optimally designed to enhance ipsiversive eye movements.

Temporal and region-specific requirements of αCaMKII in spatial and contextual learning.

The α isoform of the calcium/calmodulin-dependent protein kinase II (αCaMKII) has been implicated extensively in molecular and cellular mechanisms underlying spatial and contextual learning in a wide variety of species. Germline deletion of Camk2a leads to severe deficits in spatial and contextual learning in mice. However, the temporal and region-specific requirements for αCaMKII have remained largely unexplored. Here, we generated conditional Camk2a mutants to examine the influence of spatially restricted and temporally controlled expression of αCaMKII. Forebrain-specific deletion of the Camk2a gene resulted in severe deficits in water maze and contextual fear learning, whereas mice with deletion restricted to the cerebellum learned normally. Furthermore, we found that temporally controlled deletion of the Camk2a gene in adult mice is as detrimental as germline deletion for learning and synaptic plasticity. Together, we confirm the requirement for αCaMKII in the forebrain, but not the cerebellum, in spatial and contextual learning. Moreover, we highlight the absolute requirement for intact αCaMKII expression at the time of learning.

Apolipoprotein B-48 and late graft failure in kidney transplant recipients.

Introduction: Transplant vasculopathy resembles atherosclerotic plaque formation and is a major contributor to late graft failure in kidney transplant recipients (KTR). Remnant lipoproteins and associated triglycerides are causal risk factors for atherosclerotic plaques and have been implicated in late kidney graft failure. However, whether remnants derived from liver (containing apolipoprotein [apo] B100) or intestine (containing apoB48) are clinically more important is unclear. The current study investigated the association between baseline fasting apoB48 levels and late kidney graft failure. Methods: 481 KTR with a functioning graft for at least 1 year were included in this retrospective, observational longitudinal single center cohort study. The primary endpoint was death-censored late graft failure, defined as need for initiation of dialysis or re-transplantation. ApoB48 was measured by enzyme-linked immunosorbent assay. Results: During a median follow-up of 9.5 years, 61 KTR developed graft failure (12.7%). At baseline, KTR with higher apoB48 levels had lower eGFR (P < .001), lower high-density lipoprotein (HDL) cholesterol (P < .001), increased triglycerides (P < .001) and used cyclosporine more frequently (P = .003). Cox regression showed that higher baseline apoB48 was associated with higher risk of late graft failure [hazard ratio (95% confidence interval), 1.59 (1.22, 2.07), P < .001], independent of stepwise adjustment for potential confounders, including age and sex, immunosuppression type and proteinuria, triglycerides, and waist circumference (fully adjusted HR, 1.78 (1.29, 2.47), P < .001]. Conclusion: ApoB48 is strongly associated with late graft failure, independent of potential confounders. Since apoB48-containing lipoproteins originate from the intestine, this study provides a rationale for considering pharmacological interventions targeting lipid absorption to improve graft outcome.

Supine counterstrain technique for rhomboid tender point.

Because poor posture is a common instigating factor in back, shoulder, and neck pain, the rhomboid muscles should be considered in a complete physical evaluation. Previous techniques for treating a rhomboid tender point have addressed only one of the two main actions of the muscle, specifically retraction of the scapula utilizing shoulder abduction. This modified supine counterstrain technique for the rhomboid tender point incorporates both scapular retraction as well as superior, medial rotation of the inferior border of the scapula without abduction, providing a comprehensive treatment to accommodate patients with shoulder movement restrictions. This article discusses indications, contraindications, treatment, and a list of problem-solving strategies for the rhomboid tender point.

A superficial dissection approach to the sphenopalatine (pterygopalatine) ganglion to emphasize osteopathic clinical relevance.

The sphenopalatine (pterygopalatine) ganglion (SPG) is the most superficial ganglia to manipulate from the oral cavity. It has parasympathetic and sensory fibers directly affecting the paranasal sinuses as well as the palatine, nasal, pharyngeal, and lacrimal glands. The SPG can be manipulated intraorally by students and physicians utilizing osteopathic manipulative treatment (OMT) to relieve congestion associated with sinusitis, allergies, headaches, and upper respiratory infections. Within osteopathic medical education programs, students have anecdotally had difficulty identifying this ganglion due to its deep anatomic location and lack of direct visualization. In this article, we discuss that cadaveric dissection with a superficial to deep approach to the SPG has the ability to allow medical students and physicians to better understand the three-dimensional location and osteopathic clinical relevance of this ganglion.

Counterstrain technique for anterior and middle scalene tender point.

When a patient presents with head, neck, or respiratory concerns, the scalene muscles are not commonly considered. However, somatic dysfunctions of the anterior/middle scalenes (AMS) can be contributing to or causing these medical concerns. Although tender points within the scalene muscles have been documented within the muscle belly, they have not been documented at the insertion site. This article details how to diagnose and treat an AMS tender point with an efficient technique that requires minimal exertion and maximal comfort for both the physician and patient at a new tender point location. This article also discusses the importance of this tender point and provides a list of additional somatic dysfunctions that may be used to problem-solve a scalene tender point that fails to correct.

Adult Camk2a gene reinstatement restores the learning and plasticity deficits of Camk2a knockout mice.

With the recent findings that mutations in the gene encoding the α-subunit of calcium/calmodulin-dependent protein kinase II (CAMK2A) causes a neurodevelopmental disorder (NDD), it is of great therapeutic relevance to know if there exists a critical developmental time window in which CAMK2A needs to be expressed for normal brain development, or whether expression of the protein at later stages is still beneficial to restore normal functioning. To answer this question, we generated an inducible Camk2a mouse model, which allows us to express CAMK2A at any desired time. Here, we show that adult expression of CAMK2A rescues the behavioral and electrophysiological phenotypes seen in the Camk2a knock-out mice, including spatial and conditional learning and synaptic plasticity. These results suggest that CAMK2A does not play a critical irreversible role in neurodevelopment, which is of importance for future therapies to treat CAMK2A-dependent disorders.

Rheb is essential for murine development.

Ras homolog enriched in brain (Rheb) couples growth factor signaling to activation of the target of rapamycin complex 1 (TORC1). To study its role in mammals, we generated a Rheb knockout mouse. In contrast to mTOR or regulatory-associated protein of mTOR (Raptor) mutants, the inner cell mass of Rheb(-/-) embryos differentiated normally. Nevertheless, Rheb(-/-) embryos died around midgestation, most likely due to impaired development of the cardiovascular system. Rheb(-/-) embryonic fibroblasts showed decreased TORC1 activity, were smaller, and showed impaired proliferation. Rheb heterozygosity extended the life span of tuberous sclerosis complex 1-deficient (Tsc1(-/-)) embryos, indicating that there is a genetic interaction between the Tsc1 and Rheb genes in mouse.