Structural Preservation Does Not Ensure Function at Sensory Ia-Motoneuron Synapses following Peripheral Nerve Injury and Repair.

Injury that severs peripheral nerves often results in long-lasting motor behavioral deficits and in reorganization of related spinal motor circuitry, neither of which reverse even after nerve regeneration. Stretch areflexia and gait ataxia, for example, emerge from a combination of factors including degeneration of Ia-motoneuron synapses between peripherally damaged Ia muscle spindle afferents and motoneurons. Based on evidence that nerve injury acts via immune responses to induce synapse degeneration, we hypothesized that suppressing inflammatory responses would preserve Ia-motoneuron connectivity and aid in restoring normal function. We tested our hypothesis by administering the anti-inflammatory agent minocycline in male and female rats following axotomy of a peripheral nerve. The connectivity of Ia-motoneuron synapses was then assessed both structurally and functionally at different time points. We found that minocycline treatment overcame the physical loss of Ia contacts on motoneurons which are otherwise lost after axotomy. While necessary for functional recovery, synaptic preservation was not sufficient to overcome functional decline expressed as smaller than normal stretch-evoked synaptic potentials evoked monosynaptically at Ia-motoneuron connections and an absence of the stretch reflex. These findings demonstrate a limited capacity of minocycline to rescue normal sensorimotor behavior, illustrating that structural preservation of synaptic connectivity does not ensure normal synaptic function.SIGNIFICANCE STATEMENT Here we demonstrate that acute treatment with the semisynthetic tetracycline anti-inflammatory agent minocycline permanently prevents the comprehensive loss of synaptic contacts made between sensory neurons and spinal motoneurons following peripheral nerve injury and eventual regeneration. Treatment failed, however, to rescue normal function of those synapses or the reflex circuit they mediate. These findings demonstrate that preventing synaptic disconnection alone is not sufficient to restore neural circuit operation and associated sensorimotor behaviors.

Effects of exercise on the sleep microarchitecture in the aging brain: A study on a sedentary sample.

Having a healthy sleep pattern plays a vital role in one's overall health. Sleep in the elderly is characterized by decreased slow-wave sleep and an increase of REM sleep. Furthermore, quantitative electroencephalographic (qEEG) studies have shown an age-related attenuation of total EEG power in sleep. However, exercise has been shown to improve sleep across all age groups. In this study, we used the Sleep Profiler™ EEG Sleep Monitor to observe EEG changes occurring during sleep following an aerobic exercise intervention. This study was done on older adults (N = 18, with only five subjects containing both pre- and post-data of sufficient quality for analysis) with an age range 60-85 years. The aerobics regimen was performed three times weekly for 12-weeks commencing with 20-min sessions. The time of each session progressed by 1-2 min/session as needed to a maximum time of 45 min per session. The macro-architecture (sleep stages) and microarchitecture (EEG) results were analyzed using MATLAB. For the microarchitecture, our results showed more deep sleep following the aerobic exercise regimen. Furthermore, for the microarchitecture, out results shows an increase in total EEG power post-exercise in both light (N1 and L1) and deep sleep (N2 and N3). These preliminary changes in sleep the microarchitecture suggest that non-pharmacologic methods might mitigate age-related EEG changes with potential implications for neurocognitive health.

Spinal Motor Circuit Synaptic Plasticity after Peripheral Nerve Injury Depends on Microglia Activation and a CCR2 Mechanism.

Peripheral nerve injury results in persistent motor deficits, even after the nerve regenerates and muscles are reinnervated. This lack of functional recovery is partly explained by brain and spinal cord circuit alterations triggered by the injury, but the mechanisms are generally unknown. One example of this plasticity is the die-back in the spinal cord ventral horn of the projections of proprioceptive axons mediating the stretch reflex (Ia afferents). Consequently, Ia information about muscle length and dynamics is lost from ventral spinal circuits, degrading motor performance after nerve regeneration. Simultaneously, there is activation of microglia around the central projections of peripherally injured Ia afferents, suggesting a possible causal relationship between neuroinflammation and Ia axon removal. Therefore, we used mice (both sexes) that allow visualization of microglia (CX3CR1-GFP) and infiltrating peripheral myeloid cells (CCR2-RFP) and related changes in these cells to Ia synaptic losses (identified by VGLUT1 content) on retrogradely labeled motoneurons. Microgliosis around axotomized motoneurons starts and peaks within 2 weeks after nerve transection. Thereafter, this region becomes infiltrated by CCR2 cells, and VGLUT1 synapses are lost in parallel. Immunohistochemistry, flow cytometry, and genetic lineage tracing showed that infiltrating CCR2 cells include T cells, dendritic cells, and monocytes, the latter differentiating into tissue macrophages. VGLUT1 synapses were rescued after attenuating the ventral microglial reaction by removal of colony stimulating factor 1 from motoneurons or in CCR2 global KOs. Thus, both activation of ventral microglia and a CCR2-dependent mechanism are necessary for removal of VGLUT1 synapses and alterations in Ia-circuit function following nerve injuries.SIGNIFICANCE STATEMENT Synaptic plasticity and reorganization of essential motor circuits after a peripheral nerve injury can result in permanent motor deficits due to the removal of sensory Ia afferent synapses from the spinal cord ventral horn. Our data link this major circuit change with the neuroinflammatory reaction that occurs inside the spinal cord following injury to peripheral nerves. We describe that both activation of microglia and recruitment into the spinal cord of blood-derived myeloid cells are necessary for motor circuit synaptic plasticity. This study sheds new light into mechanisms that trigger major network plasticity in CNS regions removed from injury sites and that might prevent full recovery of function, even after successful regeneration.