Dendritic Inhibition by Shh Signaling-Dependent Stellate Cell Pool Is Critical for Motor Learning.

Cerebellar inhibitory interneurons are important regulators of neural circuit activity for diverse motor and nonmotor functions. The molecular layer interneurons (MLIs), consisting of basket cells (BCs) and stellate cells (SCs), provide dendritic and somatic inhibitory synapses onto Purkinje cells, respectively. They are sequentially generated in an inside-out pattern from Pax2+ immature interneurons, which migrate from the prospective white matter to the ML of the cortex. However, little is known about how MLI subtype identities and pool sizes are determined, nor are their contributions to motor learning well understood. Here, we show that GABAergic progenitors fated to generate both BCs and SCs respond to the Sonic hedgehog (Shh) signal. Conditional abrogation of Shh signaling of either sex inhibited proliferation of GABAergic progenitors and reduced the number of Pax2+ cells, whereas persistent Shh pathway activation increased their numbers. These changes, however, did not affect early born BC numbers but selectively altered the SC pool size. Moreover, genetic depletion of GABAergic progenitors when BCs are actively generated also resulted in a specific reduction of SCs, suggesting that the specification of MLI subtypes is independent of Shh signaling and their birth order and likely occurs after Pax2+ cells settle into their laminar positions in an inside-out sequence. Mutant mice with reduced SC numbers displayed decreased dendritic inhibitory synapses and neurotransmission onto Purkinje cells, resulting in an impaired acquisition of eyeblink conditioning. These findings also reveal an essential role of Shh signaling-dependent SCs in regulating inhibitory dendritic synapses and motor learning.SIGNIFICANCE STATEMENT The cerebellar circuit that enables fine motor learning involves MLIs of BCs and SCs, which provide dendritic and somatic inhibitory synapses onto Purkinje cells. Little is known about how their identities and numbers are determined, nor are their specific contributions to motor learning well understood. We show that MLI subtypes are specified independent of Shh signaling and their birth orders but appear to occur in their terminal laminar positions according to the inside-out sequence. This finding challenges the current view that MLI subtypes are specified sequentially at the progenitor level. We also demonstrate that dendritic inhibition by Shh signaling-dependent SC pool is necessary for motor learning.

Labyrinthitis With Negative MRI As a Precursor to Rapidly Developing Primary CNS Lymphoma of the Cerebellopontine Angle.

Background: Few case reports have described primary central nervous system lymphoma (PCNSL) presenting as a cerebellopontine angle (CPA) lesion in HIV-positive patients. We describe a rare presentation of rapidly progressing PCNSL of the CPA/internal auditory canal (IAC) as labyrinthitis with initial negative MRI in an HIV-positive patient. Case: A 58-year-old male with well-controlled HIV presented with sudden left sensorineural hearing loss, tinnitus, and imbalance. Vestibular testing suggested an uncompensated left peripheral vestibular weakness. MRI demonstrated facial and cochleovestibular nerve enhancement within the CPA and IAC. The presumptive diagnosis of labyrinthitis was made. Two months later, he presented to his infectious disease provider with left facial weakness and disequilibrium and was treated for presumed Bell's palsy. One month later, he presented with left corneal reflex dysfunction, decreased visual acuity, diplopia, and worsening ataxia. Repeat MRI demonstrated a new 3.6 cm lesion of the left CPA/IAC with vasogenic edema. Despite location, the mass lacked the brainstem compression characteristic of other extra-axial CPA masses such as vestibular schwannoma. Flow cytometry and cytology from cerebrospinal fluid was consistent with primary central nervous system large B-cell lymphoma. Conclusions: We present a unique case of rapidly progressing PCNSL of the CPA/IAC in an HIV-positive patient, presenting initially as labyrinthitis with negative MRI followed by development of multiple cranial neuropathies and 3-month repeat MRI demonstrating a large CPA mass. In HIV-positive patients with a similar initial presentation, PCNSL should considered early in the diagnostic evaluation with close clinical monitoring and a low threshold for repeat imaging.

Effects of Lifestyle Modification on Vestibular Migraine.

OBJECTIVE: To evaluate effects of lifestyle modification on symptoms of dizziness and headache in patients diagnosed with definite vestibular migraine. STUDY DESIGN: Prospective within-participants repeated-measures study. SETTING: Otolaryngology tertiary care. PARTICIPANTS: Twenty-eight adults with definite vestibular migraine who were willing to be treated without pharmacological intervention. INTERVENTIONS: Information and instructions were provided on lifestyle modification; participants were instructed to improve restful sleep, exercise, eat at regulated mealtimes, and avoid dietary triggers. Participants were asked to maintain the modifications for at least 60 days. MAIN OUTCOME MEASURES: Two self-report inventories were used pre- and post-intervention to evaluate participants' perceived dizziness handicap and headache disability using the Dizziness Handicap Inventory and Headache Disability Inventory, respectively. Questions were also used to evaluate the extent to which participants reported compliance with lifestyle factors pre- and post-intervention. RESULTS: Significant improvement was observed after the lifestyle intervention with mean improvements in Dizziness Handicap Inventory and Headache Disability Inventory of 14.3 points. As a group, improvement in restful sleep was related to improvement in both dizziness and headache symptoms. At the individual participant level, 39% and 18% of participants reported significant reduction in dizziness handicap and headache disability, respectively. CONCLUSIONS: Lifestyle modifications are an effective intervention for symptoms of dizziness and headache in participants with definite vestibular migraine. Participants who reported a larger increase in restful sleep were more likely to also report larger improvements in dizziness handicap and headache disability. Effect sizes using the current intervention were comparable or better than some reported pharmacological interventions but less than others. Our lifestyle modification intervention produced significant improvement in dizziness for a larger percentage of individual participants and in headache for a similar percentage of participants compared to data reported with other lifestyle modification interventions. Lifestyle modifications, especially restful sleep, have the potential to reduce the impact of vestibular migraine on patients' lives, with limited risk.Clinical Trials Registration: NCT03979677.

Insight into the Etiology of Undifferentiated Soft Tissue Sarcomas from a Novel Mouse Model.

Aberrant activation of the Hedgehog signaling pathway has been linked to the formation of numerous cancer types, including the myogenic soft tissue sarcoma, embryonal rhabdomyosarcoma (eRMS). Here, we report PCG2, a novel mouse model in which human GLI2A, a constitutive activator of Hedgehog signaling, induced undifferentiated sarcomas that were phenotypically divergent from eRMS. Rather, sarcomas arising in PCG2 mice featured some characteristics that were reminiscent of Ewing sarcoma. Even though it is widely understood that Ewing sarcoma formation is driven by EWS-ETS gene fusions, a genetically defined mouse model is not well-established. While EWS-ETS gene fusions were not present in PCG2 sarcomas, precluding their designation as Ewing sarcoma, we did find that GLI2A induced expression of known EWS-ETS gene targets essential to Ewing pathogenesis, most notably, Nkx2.2. Moreover, we found that naïve mesenchymal progenitors originate tumors in PCG2 mice. Altogether, our work provides a novel genetic mouse model, which directly connects oncogenic Hedgehog activity to the etiology of undifferentiated soft tissue sarcomas for the first time. IMPLICATIONS: The finding that activation of Gli2 transcription factor is sufficient to induce Ewing-like sarcomas provides a direct transformative role of the Hedgehog signaling pathway in undifferentiated soft tissue sarcoma.

Lkb1 regulates granule cell migration and cortical folding of the cerebellar cortex.

Cerebellar growth and foliation require the Hedgehog-driven proliferation of granule cell precursors (GCPs) in the external granule layer (EGL). However, that increased or extended GCP proliferation generally does not elicit ectopic folds suggests that additional determinants control cortical expansion and foliation during cerebellar development. Here, we find that genetic loss of the serine-threonine kinase Liver Kinase B1 (Lkb1) in GCPs increased cerebellar cortical size and foliation independent of changes in proliferation or Hedgehog signaling. This finding is unexpected given that Lkb1 has previously shown to be critical for Hedgehog pathway activation in cultured cells. Consistent with unchanged proliferation rate of GCPs, the cortical expansion of Lkb1 mutants is accompanied by thinning of the EGL. The plane of cell division, which has been implicated in diverse processes from epithelial surface expansions to gyrification of the human cortex, remains unchanged in the mutants when compared to wild-type controls. However, we find that Lkb1 mutants display delayed radial migration of post-mitotic GCPs that coincides with increased cortical size, suggesting that aberrant cell migration may contribute to the cortical expansion and increase foliation. Taken together, our results reveal an important role for Lkb1 in regulating cerebellar cortical size and foliation in a Hedgehog-independent manner.