Michelle A. Hook

Chimpanzees (Pan troglodytes) are predominantly right-handed: replication in three populations of apes.

Population-level right-handedness has historically been considered a hallmark of human evolution. Even though recent studies in chimpanzees (Pan troglodytes) have demonstrated population-level right-handedness for certain behaviors, some have questioned the validity and consistency of these findings by arguing that reported laterality effects are specific to certain colonies of apes and to those chimpanzees reared by humans. The authors report evidence of population-level right-handedness in 3 separate colonies of chimpanzees. Moreover, handedness in the 3 colonies was unrelated to the proportion of subjects that were raised by humans. This is the strongest evidence to date that population-level handedness is evident in chimpanzees and is not an artifact of human rearing.

MICRORNA DYSREGULATION FOLLOWING SPINAL CORD CONTUSION: IMPLICATIONS FOR NEURAL PLASTICITY AND REPAIR

Spinal cord injury (SCI) is medically and socioeconomically debilitating. Currently, there is a paucity of effective therapies that promote regeneration at the injury site, and limited understanding of mechanisms that can be utilized to therapeutically manipulate spinal cord plasticity. MicroRNAs (miRNAs) constitute novel targets for therapeutic intervention to promote repair and regeneration. Microarray comparisons of the injury sites of contused and sham rat spinal cords, harvested 4 and 14 days following SCI, showed that 32 miRNAs, including miR124, miR129, and miR1, were significantly down-regulated, whereas SNORD2, a translation-initiation factor, was induced. Additionally, three miRNAs including miR21 were significantly induced, indicating adaptive induction of an anti-apoptotic response in the injured cord. Validation of miRNA expression by qRT-PCR and in situ hybridization assays revealed that the influence of SCI on miRNA expression persists up to 14 days and expands both anteriorly and caudally beyond the lesion site. Specifically, changes in miR129-2 and miR146a expression significantly explained the variability in initial injury severity, suggesting that these specific miRNAs may serve as biomarkers and therapeutic targets for SCI. Moreover, the pattern of miRNA changes coincided spatially and temporally with the appearance of SOX2, nestin, and REST immunoreactivity, suggesting that aberrant expression of these miRNAs may not only reflect the emergence of stem cell niches, but also the reemergence in surviving neurons of a pre-neuronal phenotype. Finally, bioinformatics analysis of validated miRNA-targeted genes indicates that miRNA dysregulation may explain apoptosis susceptibility and aberrant cell cycle associated with a loss of neuronal identity, which underlies the pathogenesis of secondary SCI.

Instrumental Learning Within the Spinal Cord: Underlying Mechanisms and Implications for Recovery After Injury:

Using spinally transected rats, research has shown that neurons within the L4-S2 spinal cord are sensitive to response-outcome (instrumental) relations. This learning depends on a form of N-methyl-D-aspartate (NMDA)-mediated plasticity. Instrumental training enables subsequent learning, and this effect has been linked to the expression of brain-derived neurotrophic factor. Rats given uncontrollable stimulation later exhibit impaired instrumental learning, and this deficit lasts up to 48 hr. The induction of the deficit can be blocked by prior training with controllable shock, the concurrent presentation of a tonic stimulus that induces antinociception, or pretreatment with an NMDA or gamma-aminobutyric acid-A antagonist. The expression of the deficit depends on a kappa opioid. Uncontrollable stimulation enhances mechanical reactivity (allodynia), and treatments that induce allodynia (e.g., inflammation) inhibit learning. In intact animals, descending serotonergic neurons exert a protective effect that blocks the adverse consequences of uncontrollable stimulation. Uncontrollable, but not controllable, stimulation impairs the recovery of function after a contusion injury.

Peripheral inflammation undermines the plasticity of the isolated spinal cord.

Peripheral capsaicin treatment induces molecular changes that sensitize the responses of nociceptive neurons in the spinal dorsal horn. The current studies demonstrate that capsaicin also undermines the adaptive plasticity of the spinal cord, rendering the system incapable of learning a simple instrumental task. In these studies, male rats are transected at the second thoracic vertebra and are tested 24 to 48 hours later. During testing, subjects receive shock to one hindleg when it is extended (controllable stimulation). Rats quickly learn to maintain the leg in a flexed position. Rats that have been injected with capsaicin (1% or 3%) in the hindpaw fail to learn, even when tested on the leg contralateral to the injection. This learning deficit lasts at least 24 hours. Interestingly, training with controllable electrical stimulation prior to capsaicin administration protects the spinal cord against the maladaptive effects. Rats pretrained with controllable stimulation do not display a learning deficit or tactile allodynia. Moreover, controllable stimulation, combined with naltrexone, reverses the capsaicin-induced deficit. These data suggest that peripheral inflammation, accompanying spinal cord injuries, might have an adverse effect on recovery.

Population-Level Right Handedness for a Coordinated Bimanual Task in Chimpanzees: Replication and Extension in a Second Colony of Apes

The purpose of this study was to evaluate the reliability of previously published findings on hand preferences in chimpanzees by evaluating hand use in a second colony of captive chimpanzees. We assessed hand preferences for a coordinated bimanual task in 116 chimpanzees (Pan troglodytes) at the University of Texas M. D. Anderson Cancer Center and compared them to previously published findings in captive chimpanzees at the Yerkes National Primate Research Center. The new sample showed significant population-level right handedness, which is consistent with previously published findings in the Yerkes chimpanzees. Combined data on the 2 chimpanzee colonies, revealed a significant effect of rearing history on hand preference, with wild-caught chimpanzees showing less right-handedness than captive-born mother-reared chimpanzees. We discuss the results in terms of the role of early environment on the development of laterality.

Maladaptive spinal plasticity opposes spinal learning and recovery in spinal cord injury

Synaptic plasticity within the spinal cord has great potential to facilitate recovery of function after spinal cord injury (SCI). Spinal plasticity can be induced in an activity-dependent manner even without input from the brain after complete SCI. A mechanistic basis for these effects is provided by research demonstrating that spinal synapses have many of the same plasticity mechanisms that are known to underlie learning and memory in the brain. In addition, the lumbar spinal cord can sustain several forms of learning and memory, including limb-position training. However, not all spinal plasticity promotes recovery of function. Central sensitization of nociceptive (pain) pathways in the spinal cord may emerge in response to various noxious inputs, demonstrating that plasticity within the spinal cord may contribute to maladaptive pain states. In this review we discuss interactions between adaptive and maladaptive forms of activity-dependent plasticity in the spinal cord below the level of SCI. The literature demonstrates that activity-dependent plasticity within the spinal cord must be carefully tuned to promote adaptive spinal training. Prior work from our group has shown that stimulation that is delivered in a limb position-dependent manner or on a fixed interval can induce adaptive plasticity that promotes future spinal cord learning and reduces nociceptive hyper-reactivity. On the other hand, stimulation that is delivered in an unsynchronized fashion, such as randomized electrical stimulation or peripheral skin injuries, can generate maladaptive spinal plasticity that undermines future spinal cord learning, reduces recovery of locomotor function, and promotes nociceptive hyper-reactivity after SCI. We review these basic phenomena, how these findings relate to the broader spinal plasticity literature, discuss the cellular and molecular mechanisms, and finally discuss implications of these and other findings for improved rehabilitative therapies after SCI.

Intrathecal Morphine Attenuates Recovery of Function after a Spinal Cord Injury

Prior work has shown that a high dose (20 mg/kg) of systemic morphine, required to produce significant analgesia in the acute phase of a contusion injury, undermines the long-term health of treated subjects and increases lesion size. Moreover, a single dose of systemic morphine in the early stage of injury (24 h post-injury) led to symptoms of neuropathic pain 3 weeks later, in the chronic phase. The present study examines the locus of the effects using intrathecal morphine administration. Subjects were treated with one of three doses (0, 30, or 90 microg) of intrathecal morphine 24 h after a moderate contusion injury. The 90-microg dose produced significant analgesia when subjects were exposed to noxious stimuli (thermal and incremented shock) below the level of injury. Yet, despite analgesic efficacy, intrathecal morphine significantly attenuated the recovery of locomotor function and increased lesion size rostral to the injury site. A single dose of 30 or 90 microg of intrathecal morphine also decreased weight gain, and more than doubled the incidence of mortality and autophagia when compared to vehicle-treated controls. Morphine is one of the most effective pharmacological agents for the treatment of neuropathic pain and, therefore, is indispensable for the spinally injured. Treatment can, however, adversely affect the recovery process. A morphine-induced attenuation of recovery may result from increases in immune cell activation and, subsequently, pro-inflammatory cytokine concentrations in the contused spinal cord.

Group I Metabotropic Glutamate Receptors Control Metaplasticity of Spinal Cord Learning through a Protein Kinase C-Dependent Mechanism

Neurons within the spinal cord can support several forms of plasticity, including response–outcome (instrumental) learning. After a complete spinal transection, experimental subjects are capable of learning to hold the hindlimb in a flexed position (response) if shock (outcome) is delivered to the tibialis anterior muscle when the limb is extended. This response-contingent shock produces a robust learning that is mediated by ionotropic glutamate receptors (iGluRs). Exposure to nociceptive stimuli that are independent of limb position (e.g., uncontrollable shock; peripheral inflammation) produces a long-term (>24 h) inhibition of spinal learning. This inhibition of plasticity in spinal learning is itself a form of plasticity that requires iGluR activation and protein synthesis. Plasticity of plasticity (metaplasticity) in the CNS has been linked to group I metabotropic glutamate receptors (subtypes mGluR1 and mGluR5) and activation of protein kinase C (PKC). The present study explores the role of mGluRs and PKC in the metaplastic inhibition of spinal cord learning using a combination of behavioral, pharmacological, and biochemical techniques. Activation of group I mGluRs was found to be both necessary and sufficient for metaplastic inhibition of spinal learning. PKC was activated by stimuli that inhibit spinal learning, and inhibiting PKC activity restored the capacity for spinal learning. Finally, a PKC inhibitor blocked the metaplastic inhibition of spinal learning produced by a group I mGluR agonist. The data strongly suggest that group I mGluRs control metaplasticity of spinal learning through a PKC-dependent mechanism, providing a potential therapeutic target for promoting use-dependent plasticity after spinal cord injury.

Simple Reaching Is Not So Simple: Association Between Hand Use and Grip Preferences in Captive Chimpanzees

We assessed the relationship between grip preference and hand use in chimpanzees in 2 experiments. In experiment 1, we evaluated consistency in hand use and grip preference across 4 food types. The chimpanzees showed population-level right-handedness and there are significant positive associations for both hand and grip use across food types. In experiment 2, we assessed validity of hand use in relation to grip preference in 2 colonies of chimpanzees via the same methodology. Differences in hand preferences between colonies were associated with variation in the observed grip preferences. There was no evidence of rearing effects on handedness in either colony. We discuss the overall results in the context of the evolution of handedness in relation to increasing motor demands as manifest in variation on grasping behavior.

The impact of morphine after a spinal cord injury

Nociceptive stimulation, at an intensity that elicits pain-related behavior, attenuates recovery of locomotor and bladder functions, and increases tissue loss after a contusion injury. These data imply that nociceptive input (e.g., from tissue damage) can enhance the loss of function after injury, and that potential clinical treatments, such as pretreatment with an analgesic, may protect the damaged system from further secondary injury. The current study examined this hypothesis and showed that a potential treatment (morphine) did not have a protective effect. In fact, morphine appeared to exacerbate the effects of nociceptive stimulation. Experiment 1 showed that after spinal cord injury 20mg/kg of systemic morphine was necessary to induce strong antinociception and block behavioral reactivity to shock treatment, a dose that was much higher than that needed for sham controls. In Experiment 2, contused rats were given one of three doses of morphine (Vehicle, 10, 20mg/kg) prior to exposure to uncontrollable electrical stimulation or restraint alone. Despite decreasing nociceptive reactivity, morphine did not attenuate the long-term consequences of shock. Rats treated with morphine and shock had higher mortality rates, and displayed allodynic responses to innocuous sensory stimuli three weeks later. Independent of shock, morphine per se undermined recovery of sensory function. Rats treated with morphine alone also had significantly larger lesions than those treated with saline. These results suggest that nociceptive stimulation affects recovery despite a blockade of pain-elicited behavior. The results are clinically important because they suggest that opiate treatment may adversely affect the recovery of function after injury.