Ventral spinocerebellar tract neurons are essential for mammalian locomotion

Locomotion, including running, walking, and swimming, is a complex behavior enabling animals to interact with the environment. Vertebrate locomotion depends upon sets of interneurons in the spinal cord, known as the central pattern generator (CPG). The CPG performs multiple roles: pattern formation (left-right alternation and flexor-extensor alternation) and rhythm generation (the onset and frequency of locomotion). Many studies have begun to unravel the organization of the neuronal circuits underlying left-right and flexor-extensor alternation. However, despite pharmacologic, lesion, and optogenetic studies suggesting that the rhythm generating neurons are ispilaterally-projecting glutamatergic neurons, the precise cellular identification of rhythm generating neurons remains largely unknown. Traditionally, CPG networks (both pattern formation and rhythm generation) are thought to reside upstream of motor neurons, which serve as the output of the spinal cord. Recently however, it has been discovered that direct stimulation of lumbar motor neurons using the intact ex vivo neonate mouse spinal cord preparation can activate CPG networks to produce locomotor-like behavior. Furthermore, depressing motor neuron discharge decreases locomotor frequency, whereas increasing motor neuron discharge accelerates locomotor frequency, suggesting that motor neurons provide ongoing feedback to the CPG. However, the circuit mechanisms through which motor neurons can influence activity in the CPG in mammals remain unknown. Here, I used motor neurons as a means of accessing CPG interneurons by asking how motor neuron activation might induce locomotor-like activity. Through intracellular recording and morphological assays, I discovered that ventral spinocerebellar tract (VSCT) neurons are activated monosynaptically following motor neuron axon stimulation through chemical and electrical synapses. A subset of VSCT neurons were located close to or within the motor neuron nucleus. VSCT neurons were found to be excitatory, have descending spinal axon collaterals, and influence motor neuron output, suggesting that VSCT neurons are positioned advantageously to initiate and maintain locomotor-like rhythmogenesis. Intracellular recording from VSCT neurons revealed that they exhibit rhythmic activity during locomotor-like activity. VSCT neurons were found to contain the rhythmogenic pacemaker Ih current and to be connected to other VSCT neurons, at least through gap junctions. Optogenetic and chemogenetic manipulation of VSCT neuron activity provided evidence that VSCT neurons are both necessary and sufficient for the production of locomotor-like activity. Silencing VSCT neurons prevented the induction of such activity, whereas activation of VSCT neurons was capable of inducing locomotor-like activity. The production of locomotor-like activity by VSCT neuron photoactivation was dependent upon both electrical communication through gap junctions as well as the pacemaker Ih current. The evidence presented in this thesis suggests that VSCT neurons are critical components for rhythm generation in the mammalian CPG and are key mediators of locomotor activity

Control of mammalian locomotion by ventral spinocerebellar tract neurons

Locomotion is a complex behavior required for animal survival. Vertebrate locomotion depends on spinal interneurons termed the central pattern generator (CPG), which generates activity responsible for the alternation of flexor and extensor muscles and the left and right side of the body. It is unknown whether multiple or a single neuronal type is responsible for the control of mammalian locomotion. Here, we show that ventral spinocerebellar tract neurons (VSCTs) drive generation and maintenance of locomotor behavior in neonatal and adult mice. Using mouse genetics, physiological, anatomical, and behavioral assays, we demonstrate that VSCTs exhibit rhythmogenic properties and neuronal circuit connectivity consistent with their essential role in the locomotor CPG. Importantly, optogenetic activation and chemogenetic silencing reveals that VSCTs are necessary and sufficient for locomotion. These findings identify VSCTs as critical components for mammalian locomotion and provide a paradigm shift in our understanding of neural control of complex behaviors

Elucidating the neuroimmunology of traumatic brain injury: methodological approaches to unravel intercellular communication and function

The neuroimmunology of traumatic brain injury (TBI) has recently gained recognition as a crucial element in the secondary pathophysiological consequences that occur following neurotrauma. Both immune cells residing within the central nervous system (CNS) and those migrating from the periphery play significant roles in the development of secondary brain injury. However, the precise mechanisms governing communication between innate and adaptive immune cells remain incompletely understood, partly due to a limited utilization of relevant experimental models and techniques. Therefore, in this discussion, we outline current methodologies that can aid in the exploration of TBI neuroimmunology, with a particular emphasis on the interactions between resident neuroglial cells and recruited lymphocytes. These techniques encompass adoptive cell transfer, intra-CNS injection(s), selective cellular depletion, genetic manipulation, molecular neuroimaging, as well as in vitro co-culture systems and the utilization of organoid models. By incorporating key elements of both innate and adaptive immunity, these methods facilitate the examination of clinically relevant interactions. In addition to these preclinical approaches, we also detail an emerging avenue of research that seeks to leverage human biofluids. This approach enables the investigation of how resident and infiltrating immune cells modulate neuroglial responses after TBI. Considering the growing significance of neuroinflammation in TBI, the introduction and application of advanced methodologies will be pivotal in advancing translational research in this field

The Relationship Among Surgeon Experience, Complications, and Radiographic Outcomes in Spine Deformity Surgery: The Experience of a Junior Surgeon

OBJECTIVE: To examine complication rates and radiographic outcomes in patients undergoing surgery for adult spinal deformity (ASD) by a junior surgeon. METHODS: A study was conducted of a retrospective cohort of patients who underwent an open posterior interbody fusion of the thoracic and/or lumbar regions by a single surgeon for ASD between 2018 and 2022. Patient characteristics, complications, and common radiographic parameters of spinopelvic alignment were collated. RESULTS: A total of 112 patients with an average of 4.2 comorbidities underwent surgical correction of ASD. Thirty-seven patients (33.0%) experienced 52 major complications and 50 patients (44.6%) experienced 66 minor complications. Twenty-three patients (20.5%) required a revision operation. Both sagittal vertical axis (P \u3c 10) and pelvic incidence-lumbar lordosis mismatch (P \u3c 10) significantly improved postoperatively. Number of levels (P \u3c 0.05), operative time \u3e650 minutes (P \u3c 0.01), estimated blood loss \u3e1500 mL (P \u3c 0.01), length of intensive care unit stay \u3e1 day (P \u3c 0.05), and hospitalization length \u3e5 days (P \u3c 0.05) all significantly increased the risk of a major complication. No patient factors significantly increased the risk of minor complications or revision surgery. CONCLUSIONS: Observed complication and revision rates in this cohort were consistent with rates reported in the literature. No preoperative patient risk factors significantly increased risk of complications or need for revision, suggesting that no patient population is at increased risk undergoing surgery by a junior surgeon. The relatively high rate of complications observed in this cohort may be a result of high baseline morbidity

The relationship between surgeon experience, complications, and radiographic outcomes in spine deformity surgery: the experience of a junior surgeon

OBJECTIVE: To examine complication rates and radiographic outcomes in patients undergoing surgery for adult spinal deformity by a junior surgeon. METHODS: A study was conducted of a retrospective cohort of patients who underwent an open posterior interbody fusion of the thoracic and/or lumbar regions by a single surgeon for adult spinal deformity (ASD) between 2018 and 2022. Patient characteristics, complications, and common radiographic parameters of spinopelvic alignment were collated. RESULTS: 112 patients with an average of 4.2 comorbidities underwent surgical correction of ASD. 37 patients (33.0%) experienced 52 major complications and 50 patients (44.6%) experienced 66 minor complications. 23 patients (20.5%) required a revision operation. Both sagittal vertical axis (p \u3c 10) and pelvic incidence-lumbar lordosis mismatch (p \u3c 10) significantly improved postoperatively. Number of levels (p \u3c 0.05), operative time \u3e 650 minutes (p \u3c 0.01), estimated blood loss \u3e 1500mL (p \u3c 0.01), length of ICU stay \u3e 1 day (p \u3c 0.05), and hospitalization length \u3e 5 days (p \u3c 0.05) all significantly increased the risk of a major complication. No patient factors significantly increased the risk of minor complications or revision surgery. CONCLUSION: Observed complication and revision rates in this cohort were consistent with rates published in the literature. No pre-operative patient risk factors significantly increased risk of complications or need for revision, suggesting that no patient population is at increased risk undergoing surgery by a junior surgeon. The relatively high rate of complications observed in this cohort may be due to high baseline morbidity

Spinal Metastases from Colorectal Cancer at Mass General Brigham: A Twenty-Year Case Series with Literature Review

OBJECTIVE: We present an institutional case series of patients treated for colorectal carcinoma (CRC) spinal metastases to investigate the outcomes between no treatment, radiation, surgery, and surgery/radiation. METHODS: A retrospective cohort of patients with CRC spinal metastases presenting to affiliated institutions between 2001 and 2021 was identified. Information related to patient demographics, treatment modality, treatment outcomes, symptom improvement, and survival was collected by chart review. Overall survival (OS) was compared between treatments by log-rank significance testing. A literature review was conducted to identify other cases series of CRC patients with spinal metastases. RESULTS: Eighty-nine patients (mean age 58.5) with CRC spinal metastases across a mean of 3.3 levels met inclusion criteria: 14 (15.7%) received no treatment, 11 (12.4%) received surgery alone, 37 (41.6%) received radiation alone, and 27 (30.3%) received both radiation and surgery. Patients treated with combination therapy had the longest median OS of 24.7 months (range 0.6-85.9), which did not significantly differ from the median OS of 8.9 months (range 0.2-42.6) observed in patients who received no treatment (p = 0.075). Combination therapy provided objectively longer survival time in comparison to other treatment modalities but failed to reach statistical significance. The majority of patients that received treatment (n = 51/75, 68.0%) experienced some degree of symptomatic or functional improvement. CONCLUSION: Therapeutic intervention has the potential to improve the quality of life in patients with CRC spinal metastases. We demonstrate that surgery and radiation are useful options for these patients, despite their lack of objective improvement in OS

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

The hallmark of spinal muscular atrophy (SMA), an inherited disease caused by ubiquitous deficiency in the SMN protein, is the selective degeneration of subsets of spinal motor neurons. Here, we show that cell-autonomous activation of p53 occurs in vulnerable but not resistant motor neurons of SMA mice at pre-symptomatic stages. Moreover, pharmacological or genetic inhibition of p53 prevents motor neuron death, demonstrating that induction of p53 signaling drives neurodegeneration. At late disease stages, however, nuclear accumulation of p53 extends to resistant motor neurons and spinal interneurons but is not associated with cell death. Importantly, we identify phosphorylation of serine 18 as a specific post-translational modification of p53 that exclusively marks vulnerable SMA motor neurons and provide evidence that amino-terminal phosphorylation of p53 is required for the neurodegenerative process. Our findings indicate that distinct events induced by SMN deficiency converge on p53 to trigger selective death of vulnerable SMA motor neurons