Tuberous sclerosis complex is associated with a novel human tauopathy.

Tuberous sclerosis complex (TSC) is a neurogenetic disorder leading to epilepsy, developmental delay, and neurobehavioral dysfunction. The syndrome is caused by pathogenic variants in TSC1 (coding for hamartin) or TSC2 (coding for tuberin). Recently, we reported a progressive frontotemporal dementia-like clinical syndrome in a patient with a mutation in TSC1, but the neuropathological changes seen in adults with TSC with or without dementia have yet to be systematically explored. Here, we examined neuropathological findings in adults with TSC (n = 11) aged 30-58 years and compared them to age-matched patients with epilepsy unrelated to TSC (n = 9) and non-neurological controls (n = 10). In 3 of 11 subjects with TSC, we observed a neurofibrillary tangle-predominant "TSC tauopathy" not seen in epilepsy or non-neurological controls. This tauopathy was observed in the absence of pathological amyloid beta, TDP-43, or alpha-synuclein deposition. The neurofibrillary tangles in TSC tauopathy showed a unique pattern of post-translational modifications, with apparent differences between TSC1 and TSC2 mutation carriers. Tau acetylation (K274, K343) was prominent in both TSC1 and TSC2, whereas tau phosphorylation at a common phospho-epitope (S202) was observed only in TSC2. TSC tauopathy was observed in selected neocortical, limbic, subcortical, and brainstem sites and showed a 3-repeat greater than 4-repeat tau isoform pattern in both TSC1 and TSC2 mutation carriers, but no tangles were immunolabeled with MC1 or p62 antibodies. The findings suggest that individuals with TSC are at risk for a unique tauopathy in mid-life and that tauopathy pathogenesis may involve TSC1, TSC2, and related molecular pathways.

Neural activation associated with outgroup helping in adolescent rats.

Prosocial behavior, helping others in need in particular, occurs preferentially in response to the perceived distress of one's own group members or ingroup. To investigate the development of ingroup bias, neural activity during a helping test was analyzed in adolescent and adult rats. Although adults selectively released trapped ingroup members, adolescent rats helped both ingroup and outgroup members, suggesting that ingroup bias emerges in adulthood. Analysis of brain-wide neural activity, indexed by expression of the early-immediate gene c-Fos, revealed increased activity for ingroup members across a broad set of regions previously associated with empathy. Adolescents showed reduced hippocampal and insular activity and increased orbitofrontal cortex activity compared to adults. Non-helper adolescents demonstrated increased amygdala connectivity. These findings demonstrate that biases for group-dependent prosocial behavior develop with age in rats and suggest that specific brain regions contribute to prosocial selectivity, pointing to possible targets for the functional modulation of ingroup bias.

Hormonal Regulation of Oligodendrogenesis I: Effects across the Lifespan.

The brain's capacity to respond to changing environments via hormonal signaling is critical to fine-tuned function. An emerging body of literature highlights a role for myelin plasticity as a prominent type of experience-dependent plasticity in the adult brain. Myelin plasticity is driven by oligodendrocytes (OLs) and their precursor cells (OPCs). OPC differentiation regulates the trajectory of myelin production throughout development, and importantly, OPCs maintain the ability to proliferate and generate new OLs throughout adulthood. The process of oligodendrogenesis, the creation of new OLs, can be dramatically influenced during early development and in adulthood by internal and environmental conditions such as hormones. Here, we review the current literature describing hormonal regulation of oligodendrogenesis within physiological conditions, focusing on several classes of hormones: steroid, peptide, and thyroid hormones. We discuss hormonal regulation at each stage of oligodendrogenesis and describe mechanisms of action, where known. Overall, the majority of hormones enhance oligodendrogenesis, increasing OPC differentiation and inducing maturation and myelin production in OLs. The mechanisms underlying these processes vary for each hormone but may ultimately converge upon common signaling pathways, mediated by specific receptors expressed across the OL lineage. However, not all of the mechanisms have been fully elucidated, and here, we note the remaining gaps in the literature, including the complex interactions between hormonal systems and with the immune system. In the companion manuscript in this issue, we discuss the implications of hormonal regulation of oligodendrogenesis for neurological and psychiatric disorders characterized by white matter loss. Ultimately, a better understanding of the fundamental mechanisms of hormonal regulation of oligodendrogenesis across the entire lifespan, especially in vivo, will progress both basic and translational research.

Hormonal Regulation of Oligodendrogenesis II: Implications for Myelin Repair.

Alterations in myelin, the protective and insulating sheath surrounding axons, affect brain function, as is evident in demyelinating diseases where the loss of myelin leads to cognitive and motor dysfunction. Recent evidence suggests that changes in myelination, including both hyper- and hypo-myelination, may also play a role in numerous neurological and psychiatric diseases. Protecting myelin and promoting remyelination is thus crucial for a wide range of disorders. Oligodendrocytes (OLs) are the cells that generate myelin, and oligodendrogenesis, the creation of new OLs, continues throughout life and is necessary for myelin plasticity and remyelination. Understanding the regulation of oligodendrogenesis and myelin plasticity within disease contexts is, therefore, critical for the development of novel therapeutic targets. In our companion manuscript, we review literature demonstrating that multiple hormone classes are involved in the regulation of oligodendrogenesis under physiological conditions. The majority of hormones enhance oligodendrogenesis, increasing oligodendrocyte precursor cell differentiation and inducing maturation and myelin production in OLs. Thus, hormonal treatments present a promising route to promote remyelination. Here, we review the literature on hormonal regulation of oligodendrogenesis within the context of disorders. We focus on steroid hormones, including glucocorticoids and sex hormones, peptide hormones such as insulin-like growth factor 1, and thyroid hormones. For each hormone, we describe whether they aid in OL survival, differentiation, or remyelination, and we discuss their mechanisms of action, if known. Several of these hormones have yielded promising results in both animal models and in human conditions; however, a better understanding of hormonal effects, interactions, and their mechanisms will ultimately lead to more targeted therapeutics for myelin repair.