Behavioral recovery after a spinal deafferentation injury in monkeys does not correlate with extent of corticospinal sprouting

Crowley, Matthew; Lilak, Alayna; Garner, Joseph P.; Darian‐Smith, Corinna

doi:10.1016/j.bbr.2021.113533

Cited by 3 publications

(8 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additional data from all three monkeys were used in other studies. M1603 was used in an investigation looking at corticospinal and primary afferent inputs to the dorsal horn (Fisher et al., 2020), while M1804 and M1805 were sedated periodically during the recovery period as part of another study on sensory perception (unpublished), and behavioral data were reported in a separate manuscript (Crowley et al., 2021).…”

Section: Methodsmentioning

confidence: 99%

“…This involved a laminectomy, electrophysiological recordings, and the transection of targeted dorsal rootlets and the dorsal column (see below, and Figure 1). Recovery took place over 4–6 months, during which animals were trained and assessed performing a manual dexterity task to document the resulting deficit and recovery (reported in Crowley et al., 2021; Fisher et al, 2020). One week before perfusion, monkeys were sedated briefly to make injections of cholera toxin subunit B (CT‐B) into their hands.…”

Section: Methodsmentioning

confidence: 99%

“…Associated boxplots show the spread of data for each group. The box represents the 25th-75th quartile range, the center line is the median, and whiskers mark the 10th and 90th percentiles behaviorally these monkeys had an initial deficit in manual dexterity, and then over 2-3 months they recovered their ability to perform a retrieval task at pre-lesion speed, albeit with a slightly altered digit posture (Crowley et al, 2021;Fisher et al, 2020). Clearly, the tiny proportion of inputs from the hand that were spared by the lesion were able to support the functional recovery observed.…”

Section: Relating Cutaneous and Proprioceptive Input Distributions Wi...mentioning

confidence: 99%

“…These data were for other studies and are not reported here. *Used for behavioral analysis following the DRL/DCL (Crowley et al, 2021;Fisher et al, 2020).…”

Section: Animalsmentioning

confidence: 99%

“…In combination with loss of tone, these factors can severely impair movement of the digits. Some degree of behavioral recovery typically occurs over the postlesion weeks and months (Crowley et al., 2021; Darian‐Smith & Ciferri, 2005; Qi et al., 2013; Rosenzweig et al., 2010; Vierck, 1982). This functional recovery requires that spared sensory and motor connections reorganize over time, though exactly how this happens at the cellular level remains unclear.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Small sensory spinal lesions that affect hand function in monkeys greatly alter primary afferent and motor neuron connections in the cord

Fisher

Garner

Darian‐Smith

2022

J of Comparative Neurology

Self Cite

View full text Add to dashboard Cite

Small sensory spinal injuries induce plasticity across the neuraxis, but little is understood about their effect on segmental connections or motor neuron (MN) function.Here, we begin to address this at two levels. First, we compared afferent input distributions from the skin and muscles of the digits with corresponding MN pools to determine their spatial relationship, in both the normal state and 4-6 months after a unilateral dorsal root/dorsal column lesion (DRL/DCL), affecting digits 1-3. Second, we looked at specific changes to MN inputs and membrane properties that likely impact functional recovery. Monkeys received a targeted unilateral DRL/DCL, and 4-6 months later, cholera toxin subunit B (CT-B) was injected bilaterally into either the distal pads of digits 1-3, or related intrinsic hand muscles, to label inputs to the cord, and corresponding MNs. In controls (unlesioned side), cutaneous and proprioceptive afferents from digits 1-3 showed different distribution patterns but similar rostrocaudal spread within the dorsal horn from C1 to T2. In contrast, MNs were distributed across just two segments (C7-8). Following the lesion, sensory inputs were significantly diminished across all 10 segments, though this did not alter MN distributions. Afferent and monoamine inputs, as well as KCC2 cotransporters, were also significantly altered on the cell membrane of CT-B labeled MNs postlesion. In contrast, inhibitory neurotransmission and perineuronal net integrity were not altered at this prechronic timepoint. Our findings indicate that even a small sensory injury can significantly impact sensory and motor spinal neurons and provide new insight into the complex process of recovery.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Relating Cutaneous and Proprioceptive Input Distributions Wi...mentioning

confidence: 99%

“…These data were for other studies and are not reported here. *Used for behavioral analysis following the DRL/DCL (Crowley et al, 2021;Fisher et al, 2020).…”

Section: Animalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Small sensory spinal lesions that affect hand function in monkeys greatly alter primary afferent and motor neuron connections in the cord

Fisher

Garner

Darian‐Smith

2022

J of Comparative Neurology

Self Cite

View full text Add to dashboard Cite

show abstract

Chronic Adaptations in the Dorsal Horn Following a Cervical Spinal Cord Injury in Primates

Fisher,

Garner,

Darian-Smith

2023

J. Neurosci.

View full text Add to dashboard Cite

Spinal cord injury (SCI) is devastating, with limited treatment options and variable outcomes. Mostin vivoSCI research has focused on the acute and early post-injury periods, and the promotion of axonal growth, so little is understood about the clinically stable chronic state, axonal growth over time, and what plasticity endures.Here, we followed animals into the chronic phase following SCI, to address this gap. Macaques received a targeted deafferentation, affecting three digits of one hand, and were divided into short (4-6 months) or long term (11-12 months) groups, based on post-injury survival times. Male monkeys were assessed behaviorally, where possible, and all exhibited an initial post-injury deficit in manual dexterity, with gradual functional recovery over two months.We previously reported extensive sprouting of somatosensory corticospinal (S1 CST) fibers in the dorsal horn in the first 5 post-injury months. Here we show that by 1 year, the S1 CST sprouting is pruned, with the terminal territory resembling control animals. This was reflected in the number of putatively ‘functional’ synapses observed, which increased over the first 4-5 months, and then returned to baseline by 1 year. Microglia density also increased in the affected dorsal horn at 4-6 months, and then decreased, but did not return to baseline by 1 year, suggesting refinement continues beyond this time.Overall, there is a long period of reorganization and consolidation of adaptive circuitry in the dorsal horn, extending well beyond the initial behavioral recovery. This provides a potential window to target therapeutic opportunities during the chronic phase.Significance statementMost preclinical studies of spinal cord injury focus on the early phases of recovery, during which the greatest behavioral improvements occur and there is significant sprouting of spared fibers. Here, we extended these observations into the chronic phase, in a primate model of spinal injury affecting hand function, to see if these changes were maintained long term. We show that following an early period of corticospinal (CST) and spared primary afferent sprouting, afferents remain stable while exuberant CST sprouts are pruned back to their baseline range. The presence and activation of microglia demonstrates that this process is driven partly by inflammation. Our findings provide important new insight into the chronic phase of recovery, and the potential for longer term plasticity.

show abstract

BDNF Influence on Adult Terminal Axon Sprouting after Partial Deafferentation

Benítez‐Temiño

Hernández

Cruz

et al. 2023

IJMS

View full text Add to dashboard Cite

BDNF is a neurotrophin family member implicated in many different neuronal functions, from neuronal survival during development to synaptic plasticity associated with processes of learning and memory. Its presence in the oculomotor system has previously been demonstrated, as it regulates afferent composition of extraocular motoneurons and their firing pattern. Moreover, BDNF expression increases after extraocular motoneuron partial deafferentation, in parallel with terminal axon sprouting from the remaining axons. To elucidate whether BDNF could play an active role in this process, we performed partial deafferentation of the medial rectus motoneurons through transection of one of the two main afferents, that is, the ascending tract of Deiters, and injected BDNF into the motoneuron target muscle, the medial rectus. Furthermore, to check whether BDNF could stimulate axon sprouting without lesions, we performed the same experiment without any lesions. Axon terminal sprouting was assessed by calretinin immunostaining, which specifically labels the remaining afferent system on medial rectus motoneurons, the abducens internuclear neurons. The results presented herein show that exogenous BDNF stimulated terminal axon growth, allowing the total recovery of synaptic coverage around the motoneuron somata. Moreover, calretinin staining in the neuropil exceeded that present in the control situation. Thus, BDNF could also stimulate axonal sprouting in the neuropil of intact animals. These results point to an active role of BDNF in plastic adaptations that take place after partial deafferentation.

show abstract

Behavioral recovery after a spinal deafferentation injury in monkeys does not correlate with extent of corticospinal sprouting

Cited by 3 publications

References 30 publications

Small sensory spinal lesions that affect hand function in monkeys greatly alter primary afferent and motor neuron connections in the cord

Small sensory spinal lesions that affect hand function in monkeys greatly alter primary afferent and motor neuron connections in the cord

Chronic Adaptations in the Dorsal Horn Following a Cervical Spinal Cord Injury in Primates

BDNF Influence on Adult Terminal Axon Sprouting after Partial Deafferentation

Contact Info

Product

Resources

About