Biology subjects

Jaffe, D. A.

Publications and source records attributed to Jaffe, D. A..

4 recordsLinked to original sources

bioRxiv2026

Recruitment of intrasegmental and propriospinal interneuron networks of forelimb motor circuitry in chronic cervical contusion spinal cord injury

Cervical spinal cord injury (SCI) disrupts descending supraspinal input and spinal networks controlling upper extremity motor function, making recovery of arm and hand function a major priority for affected individuals. The vast majority of regenerative strategies have been studied during the acute and sub-acute phases following SCI, while therapeutic testing remains limited for chronic injury, when persistent barriers significantly limit circuit remodeling. We asked whether pharmacologic enhancement of neuronal-intrinsic axon growth capacity through PTEN inhibition could promote forelimb motor recovery and circuit plasticity in a rodent model of chronic cervical SCI. Following C5 hemi-contusion, female rats underwent behavioral testing of forelimb motor function and received PTEN antagonist peptide (PAP) beginning at a chronic time point, and the trans-synaptic tracer, pseudorabies virus (PRV), was injected into ipsilesional triceps to trace forelimb-associated motor circuitry. PAP selectively improved forelimb usage during cylinder paw-preference testing, but not strength, sensorimotor, or gait-related forelimb measures. PAP increased recruitment of PRV-traced local-projecting and propriospinal interneuron networks. In addition, PAP enhanced synaptic input to these recruited propriospinal interneurons, raising the possibility that spared descending pathways may contribute to recovery through spinal relay circuits. Lastly, we mapped the supraspinal connectome providing descending input from brainstem to the lower motor neurons innervating forelimb muscle, and we determined how this connectome was impacted both by SCI and PAP. Together, these findings show that, even in chronic SCI, pharmacological PTEN inhibition can promote forelimb functional recovery and significant circuit remodeling, with spinal interneuron networks emerging as a key site of PAP-induced plasticity.

neuroscience↗

bioRxiv2026

Intrasegmental and propriospinal pre-phrenic interneuron circuitry in intact CNS and following cervical spinal cord injury

Cervical spinal cord injury (SCI) disrupts descending respiratory circuitry, resulting in debilitating and often persistent ventilatory deficits. Respiratory drive emerges within medulla from the rostral ventral respiratory group (rVRG), whose neurons project to C3-C6 phrenic motor neurons (PhMNs), which then innervate diaphragm, the primary muscle of inspiration. Though rVRG neurons make extensive monosynaptic connection with PhMNs, rVRG input to PhMNs can also be relayed through pre-phrenic interneurons (PP-INs) via polysynaptic pathways. However, the neuroanatomical connectivity between PP-INs and PhMNs remains incompletely understood. In both uninjured rats and the C2 hemisection (C2HS) model of cervical SCI, we performed tracing of PP-INs that were synaptically connected to PhMNs located in rostral (C3-C4) or caudal (C5-C6) portions of the phrenic nucleus by unilaterally injecting retrograde trans-synaptic tracer, pseudorabies (PRV), selectively into ventral or dorsal regions of hemi-diaphragm. We quantified numbers of PRV-labeled PP-INs individually at segments across cervical spinal cord, including separately in dorsal horn, intermediate gray, and ventral horn. We found that PP-INs are widespread throughout C1-C7 spinal cord in the uninjured condition. These PP-INs have a predominant intrasegmental connectivity pattern with PhMNs, though significant numbers of longer distance projecting propriospinal PP-INs also exist both rostral and caudal to the PhMN pool. Furthermore, while PP-INs connect both ipsilaterally and contralaterally with PhMNs, there is a strong bias to ipsilateral projection. C2HS induced major disconnection between PhMNs and ipsilesional propriospinal PP-INs located rostral to the SCI, but conversely induced limited plasticity in connectivity of intrasegmental PP-INs located within C3-C6 spinal cord. These findings greatly improve our knowledge about PP-IN circuitry and also provide important information to aid in developing approaches to target PP-IN plasticity for promoting spinal cord repair.

neuroscience↗

bioRxiv2026

Neuronal EphB2 signaling drives persistent neuropathic pain following spinal cord injury

Neuropathic pain after spinal cord injury reflects persistent hyperexcitability in the spinal cord dorsal horn, yet the molecular drivers sustaining this maladaptive state are unknown. Using an antibody microarray of dorsal horn tissue from mice six weeks after cervical contusion spinal cord injury, we found persistent upregulation of Eph-ephrin signaling, including increased EphB1, EphB2 and EphB3 expression and phosphorylation. Reversible chemogenetic inhibition of EphB kinase activity, using an EphB1/2/3 analog-sensitive knock-in mouse, selectively reversed established mechanical allodynia without affecting thermal hyperalgesia or motor function and also shifted dorsal horn signaling away from pain sensitization-associated pathways. Among EphB receptors, EphB2 showed the most consistent and robust injury-induced increase in expression within dorsal horn. Although EphB2 transcript levels increased in both dorsal horn neurons and astrocytes, conditional deletion of EphB2 only in dorsal horn neurons, but not in astrocytes, reversed established mechanical allodynia and reduced dorsal horn neuronal activation. These findings identify EphB signaling, and neuronal EphB2 in particular, as a mechanism that actively maintains pain hypersensitivity after spinal cord injury.

neuroscience↗

bioRxiv2024

PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury

High spinal cord injury (SCI) leads to persistent and debilitating compromise in respiratory function. Cervical SCI not only causes the death of phrenic motor neurons (PhMNs) that innervate the diaphragm, but also damages descending respiratory pathways originating in the rostral ventral respiratory group (rVRG) located in the brainstem, resulting in denervation and consequent silencing of spared PhMNs located caudal to injury. It is imperative to determine whether interventions targeting rVRG axon growth and respiratory neural circuit reconnection are efficacious in chronic cervical contusion SCI, given that the vast majority of individuals are chronically-injured and most cases of SCI involve contusion-type damage to the cervical region. We therefore employed a clinically-relevant rat model of chronic cervical hemicontusion to test therapeutic manipulations aimed at reconstructing damaged rVRG-PhMN-diaphragm circuitry to achieve recovery of respiratory function. At a chronic time point post-injury, we systemically administered: an antagonist peptide directed against phosphatase and tensin homolog (PTEN), a central inhibitor of neuron-intrinsic axon growth potential; an antagonist peptide directed against receptor-type protein tyrosine phosphatase sigma (PTP{sigma}), another important negative regulator of axon growth capacity; or a combination of these two peptides. PTEN antagonist peptide (PAP4) promoted partial recovery of diaphragm motor activity out to nine months post-injury, while PTP{sigma} peptide did not impact diaphragm function after cervical SCI. Furthermore, PAP4 promoted robust growth of descending bulbospinal rVRG axons caudal to the injury within the denervated portion of the PhMN pool, while PTP{sigma} peptide did not affect rVRG axon growth at this location that is critical to control of diaphragmatic respiratory function. In conclusion, we find that, when PTEN inhibition is targeted at a chronic time point following cervical contusion that is most relevant to the SCI clinical population, our non-invasive PAP4 strategy can successfully promote significant regrowth of damaged respiratory neural circuitry and also partial recovery of diaphragm motor function. HIGHLIGHTSO_LIPTEN antagonist peptide promotes partial diaphragm function recovery in chronic cervical contusion SCI. C_LIO_LIPTP{sigma} inhibitory peptide does not impact diaphragm function recovery in chronic cervical contusion SCI. C_LIO_LIPTEN antagonist peptide promotes growth of bulbospinal rVRG axons in chronic cervical contusion SCI. C_LIO_LIPTP{sigma} peptide does not affect rVRG axon growth in chronic cervical contusion SCI. C_LI

neuroscience↗