Experience-dependent structural plasticity in cortex heterotopic to focal sensorimotor cortical damage

Structural plasticity following focal neocortical damage in adult rats has recently been found to be sensitive to postinjury rehabilitative training. Experience on a complex motor skills task, the acrobatic task, after unilateral lesions of the forelimb representation region of the sensorimotor cortex (FLsmc) enhanced synaptic structural changes in the cortex contralateral and homotopic to the lesions. Using tissue from this previous study, the present study examined whether a heterotopic region of the sensorimotor cortex of either hemisphere, the hindlimb representation area (HLsmc), would undergo structural changes following unilateral FLsmc lesions and whether these changes would also be sensitive to postinjury training on the acrobatic task. Stereological methods for light and electron microscopy were used to assess structural changes in lesion or sham-operated rats following 28 days of postoperative acrobatic training or simple repetitive exercise (motor controls). In the HLsmc contralateral to the lesions of rats receiving acrobatic training, there was a subtle, but significant, increase in cortical volume and in layer II/III neuropil and dendritic volume per neuron in comparison to shams. In rats receiving simple exercise after the lesions, these changes were not significantly different from shams. Acrobatic training also prevented a loss of cortical volume in the HLsmc adjacent to the lesion in comparison to shams. These data suggest that behavioral training following cortical injury facilitates structural plasticity in behaviorally relevant areas of the neocortex other than the homotopic cortex contralateral to the lesion. This structural plasticity might be relevant to the development of behavioral compensation after cortical injury.     

Does prenatal nicotine exposure alter the brain's response to nicotine in adolescence? A neuroanatomical analysis

This study examined changes in dendritic morphology and spine density in multiple brain regions [Zilles' areas: (i) the Cg3 region of the anterior cingulate cortex or the medial prefrontal cortex, layer III (Cg3); (ii) the dorsal agranular insular cortex, layer III (AID); (iii) the PAR I region of the parietal cortex, layer III (Par1) and (iv) the nucleus accumbens (NAc)]of Long–Evans rats following exposure to nicotine prenatally, in late adolescence, or both prenatally and in adolescence. Prenatal nicotine exposure induced enduring changes in neuroanatomical organisation that varied between male and female offspring, with males exhibiting increased dendritic complexity of neurons in AID and NAc whereas females experienced increased dendritic complexity in Par1 but decreased dendritic complexity of neurons in NAc. Similarly, nicotine given in late adolescence dramatically reorganised neural circuitry of both male and female offspring, with males exhibiting decreased dendritic complexity of neurons in Par1 and Cg3 but increased dendritic complexity in AID, and females exhibiting decreased dendritic complexity in Cg3 and NAc but increased complexity in AID. Exposure to nicotine both prenatally and in adolescence produced few neuroanatomical parameters that demonstrated a prenatal experience × adolescent drug administration interaction. Females showed additive effects in Par1, Cg3 and NAc whereas males demonstrated additive effects only in AID. Thus, the timing of nicotine exposure produced differential effects on cerebral organisation in a regionally specific manner.     

Environmental complexity has different effects on the structure of neurons in the prefrontal cortex versus the parietal cortex or nucleus accumbens

Complex housing has been used widely as a model of experience-dependent change. Animals housed in complex environments typically show synaptogenesis throughout the sensory and motor cortex as well as the striatum and hippocampus, and thus it is generally assumed that such changes are likely to be found throughout the cerebrum. The purpose of the present study was to determine whether persistent alterations of dendritic morphology would be found in two regions that had previously not been examined, namely, the medial prefrontal region (Cg3) and nucleus accumbens (NAcc). The results show that housing female rats in complex environments for 3.5 months increased dendritic arborization on medium spiny neurons in the NAcc and on pyramidal cells in the somatosensory cortex (Par 1), but not in Cg3. Environmental complexity increased spine density in all three areas, however. The failure to find increased dendritic length or branching in Cg3 was unexpected. Thus, the data suggest that complex housing may not engage prefrontal neurons in the same manner as neurons in sensory or motor areas. It appears that complex housing may not produce generalized changes in cerebral morphology. The data further suggest that it is prudent to measure both dendritic length and spine density in studies of experience-dependent effects on synaptic plasticity.     

FGF-2 induces behavioral recovery after early adolescent injury to the motor cortex of rats

Motor cortex injuries in adulthood lead to poor performance in behavioral tasks sensitive to limb movements in the rat. We have shown previously that motor cortex injury on day 10 or day 55 allow significant spontaneous recovery but not injury in early adolescence (postnatal day 35 “P35”). Previous studies have indicated that injection of basic fibroblast growth factor (FGF-2) enhances behavioral recovery after neonatal cortical injury but such effect has not been studied following motor cortex lesions in early adolescence. The present study undertook to investigate the possibility of such behavioral recovery. Rats with unilateral motor cortex lesions were assigned to two groups in which they received FGF-2 or bovine serum albumin (BSA) and were tested in a number of behavioral tests (postural asymmetry, skilled reaching, sunflower seed manipulation, forepaw inhibition in swimming). Golgi-Cox analysis was used to examine the dendritic structure of pyramidal cells in the animals’ parietal (layer III) and forelimb (layer V) area of the cortex. The results indicated that rats injected with FGF-2 (but not BSA) showed significant behavioral recovery that was associated with increased dendritic length and spine density. The present study suggests a role for FGF-2 in the recovery of function following injury during early adolescence.     

Lesion size‐dependent synaptic and astrocytic responses in cortex contralateral to infarcts in middle‐aged rats

In young adult rats, unilateral lesions of the sensorimotor cortex lead to neuronal structural plasticity and synaptogenesis in the contralateral motor cortex, which is connected to the lesion site by transcallosal fibers. The contralesional neural plasticity varies with lesion size and results from the convergence of denervation‐induced reactive plasticity and behavioral asymmetries. It was unknown whether similar effects occur in older animals. Furthermore, the coordination of synaptic responses with that of perisynaptic astrocytes had not been investigated. In this study, middle‐aged rats (14–16 months old) were given sham‐operations or unilateral ischemic lesions of the sensorimotor cortex. Fifty days later, numerical densities of neurons and synapses and morphological characteristics of astrocytic processes in layer V of the contralesional motor cortex were measured using stereological light and electron microscopy methods. Lesions resulted in behavioral asymmetries, but no significant synapse addition in the contralesional motor cortex. Synapse number per neuron was negatively correlated with lesion size and reduced opposite larger lesions compared with smaller ones. Astrocytic changes were also lesion size‐dependent. Astrocytic hypertrophy was observed only after smaller lesions and was associated with greater coverage and greater numbers of synapses. These findings are consistent with those in younger rats indicating an inverse relationship between lesion size and adaptive neuronal restructuring in denervated cortex. However, they indicate that the synaptogenic reaction to this lesion is relatively limited in older animals. Finally, the results indicate that structural plasticity of perisynaptic astrocytes parallels, and could play a role in shaping, synaptic responses to postischemic denervation. Synapse 64:659–671, 2010. © 2010 Wiley‐Liss, Inc.     

Is there an optimal age for recovery from motor cortex lesions? II. behavioural and anatomical consequences of unilateral motor cortex lesions in perinatal, infant, and adult rats

Purpose: The purpose of this study was to compare the behavioural and anatomical effects of unilateral motor cortex ablation in neonatal, infant, and adult rats. Methods: Rats were given unilateral lesions of the motor cortex on the day of birth (P1), at ten days of age (P10), or in adulthood. They were trained on several motor tasks (skilled forelimb reaching, beam traversing, tongue extension), general motor activity, and a test of spatial learning (Morris water task). Results: Although all lesion groups were equally impaired at skilled reaching with the forelimb contralateral to the lesion, rats with P1 lesions also were impaired at traversing a narrow beam and at learning the Morris task. Gross anatomical analyses revealed that the P1 rats had smaller brains than the other groups, a result that may account for the larger behavioural deficits in the P1 group. Analysis of Golgi-Cox stained neurons showed that relative to control groups, all lesion groups showed an increase in dendritic length in the basilar dendrites of layer III pyramidal cells and, paradoxically a decrease in length of the apical dendrites of the same cells. Conclusions: The bilateral alterations in dendritic organization following the motor cortex lesions suggest that there has been a bilateral reor-ganization of intrinsic cortical connectivity following motor cortex lesions at any age. These alterations in connectivity are likely not identical in the young and adult animals, however, because relative to controls, both the young operated groups, but not the adult group, showed a bilat-eral drop in spine density in the basilar dendrites of layer V pyramidal cells. These findings are discussed with respect to the idea that there may be critical ages in development in which animals can use anatomical modifications to compensate for deficits produced by cortical injury.     

Is there an optimal age for recovery from motor cortex lesions? II. behavioural and anatomical consequences of unilateral motor cortex lesions in perinatal, infant, and adult rats

Purpose: The purpose of this study was to compare the behavioural and anatomical effects of unilateral motor cortex ablation in neonatal, infant, and adult rats. Methods: Rats were given unilateral lesions of the motor cortex on the day of birth (P1), at ten days of age (P10), or in adulthood. They were trained on several motor tasks (skilled forelimb reaching, beam traversing, tongue extension), general motor activity, and a test of spatial learning (Morris water task). Results: Although all lesion groups were equally impaired at skilled reaching with the forelimb contralateral to the lesion, rats with P1 lesions also were impaired at traversing a narrow beam and at learning the Morris task. Gross anatomical analyses revealed that the P1 rats had smaller brains than the other groups, a result that may account for the larger behavioural deficits in the P1 group. Analysis of Golgi-Cox stained neurons showed that relative to control groups, all lesion groups showed an increase in dendritic length in the basilar dendrites of layer III pyramidal cells and, paradoxically a decrease in length of the apical dendrites of the same cells. Conclusions: The bilateral alterations in dendritic organization following the motor cortex lesions suggest that there has been a bilateral reor-ganization of intrinsic cortical connectivity following motor cortex lesions at any age. These alterations in connectivity are likely not identical in the young and adult animals, however, because relative to controls, both the young operated groups, but not the adult group, showed a bilat-eral drop in spine density in the basilar dendrites of layer V pyramidal cells. These findings are discussed with respect to the idea that there may be critical ages in development in which animals can use anatomical modifications to compensate for deficits produced by cortical injury.     

Modulation of dendritic spine remodeling in the motor cortex following spinal cord injury: effects of environmental enrichment and combinatorial treatment with transplants and neurotrophin-3

Incomplete spinal cord injury (SCI) elicits structural plasticity of the spared motor system, including the motor cortex, which may underlie some of the spontaneous recovery of motor function seen after injury. Promoting structural plasticity may become an important component of future strategies to improve functional outcomes. We have recently observed dynamic changes in the density and morphology of dendritic spines in the motor cortex following SCI. The present study sought to test whether SCI-induced changes in spine density and morphology could be modulated by potential strategies to enhance functional recovery. We examined the effects of enriched environment, transplants, and neurotrophin-3 on the plasticity of synaptic structures in the motor cortex following SCI. Housing rats in an enriched environment increased spine density in the motor cortex regardless of injury. SCI led to a more slender and elongated spine morphology. Enriched housing mitigated the SCI-induced morphological alterations, suggesting that the environmental modification facilitates maturation of synaptic structures. Transplantation of embryonic spinal cord tissue and delivery of neurotrophin-3 at the injury site further increased spine density when combined with enriched housing. This combinatorial treatment completely abolished the injury-induced changes, restoring a preinjury pattern of spine morphology. These results demonstrated that remodeling of dendritic spines in the motor cortex after SCI can be modulated by enriched housing, and the combinatorial treatment with embryonic transplants and neurotrophin-3 can potentiate the effects of enriched housing. We suggest that synaptic remodeling processes in the motor cortex can be targeted for an intervention to enhance functional recovery after SCI.     

The behavioral and dendritic growth effects of focal sensorimotor cortical damage depend on the method of lesion induction

Using different models of focal cortical injury in adult rats, the neural structural and behavioral outcomes of unilateral lesions of the forelimb representation of the sensorimotor cortex (SMC) were assessed. Lesions were produced using either electrolytic, aspiration, or combined ('electroaspiration') techniques. Measurements of dendritic arborization in layer V of the motor cortex opposite the lesion revealed a growth of pyramidal neuron dendritic processes following electrolytic lesions in comparison to shams. This effect was not found in either the aspiration or electroaspiration lesion groups. Behaviorally, animals in all lesion groups developed a hyper-reliance on the forelimb ipsilateral to the lesion and proportionate disuse of the contralateral (impaired) forelimb for postural support behaviors. In comparison to sham-operated animals, the initial asymmetries in behaviors expressed during movement were similar between lesion groups, but were less enduring following electrolytic lesions than following aspiration and electroaspiration lesions. Furthermore, both aspiration lesion groups had more prevalent adduction of the impaired forelimb than the electrolytic-only lesion rats. Thus, cortical aspiration resulted in more severe and enduring forelimb impairments than the electrolytic lesions, despite similar lesion sizes, as assessed using cortical volume measures. These findings suggest that the aspiration lesion procedures, at least as performed in the present study, exacerbate the behavioral effects of focal cortical injury and limit compensatory plasticity in the contralateral cortex.     

Steroid hormones and maternal experience interact to induce glial plasticity in the cingulate cortex

Neocortical plasticity is not usually associated with changes in reproductive function. However, we have shown a six to 10-fold increase in the number of astrocytes labeled with glial fibrillary acidic protein (GFAP) and astrocytic basic fibroblast growth factor or FGF-2 (bFGF) in the cingulate cortex area 2 (Cg2) in postpartum rats, indicative of changes in connectivity in this area. In the present studies, we investigated the necessary and sufficient stimuli for these changes to occur. We show that 3 h of maternal experience combined with a hormonal treatment that mimics late pregnancy induces the astrocytic changes in Cg2 in virgin rats. The extent of these changes was similar to those of postpartum females. Sensitized virgin females did not show any astrocytic changes after 3 h of maternal behavior, suggesting that a similar amount of maternal experience alone is not sufficient to increase astrocytic bFGF- and GFAP-immunoreactivity in Cg2. Consistent with these data, eliminating early maternal experience by removing pups immediately postpartum abolishes the increased bFGF and GFAP protein expression in the cingulate cortex. These results suggest that maternal experience and hormonal state interact to produce astrocytic remodeling in the Cg2. The current results are consistent with a role for the cingulate cortex in maternal responsivity as suggested by early lesion studies in rats and more recent imaging studies in humans.     

Role of adaptive plasticity in recovery of function after damage to motor cortex.

Based upon neurophysiologic, neuroanatomic, and neuroimaging studies conducted over the past two decades, the cerebral cortex can now be viewed as functionally and structurally dynamic. More specifically, the functional topography of the motor cortex (commonly called the motor homunculus or motor map), can be modified by a variety of experimental manipulations, including peripheral or central injury, electrical stimulation, pharmacologic treatment, and behavioral experience. The specific types of behavioral experiences that induce long-term plasticity in motor maps appear to be limited to those that entail the development of new motor skills. Moreover, recent evidence demonstrates that functional alterations in motor cortex organization are accompanied by changes in dendritic and synaptic structure, as well as alterations in the regulation of cortical neurotransmitter systems. These findings have strong clinical relevance as it has recently been shown that after injury to the motor cortex, as might occur in stroke, post-injury behavioral experience may play an adaptive role in modifying the functional organization of the remaining, intact cortical tissue.     

Multiple synapse formation in the motor cortex opposite unilateral sensorimotor cortex lesions in adult rats.

Unilateral damage to the forelimb region of the sensorimotor cortex (FLsmc) in adult rats has previously been found to result in dendritic growth and synaptogenesis in layer V of the contralateral motor cortex. The neuronal growth appears to be mediated in part by lesion-induced changes in the use of the forelimbs. Whether these neuronal changes involve alterations in the structure and/or configuration of synaptic connections in layer V has not previously been investigated. The present study used stereological measures to characterize structural alterations in axonal processes and synaptic connections using electron micrographs generated in a previous study of the motor cortex contralateral to FLsmc lesions. Of primary interest were synapses formed by multiple synaptic boutons (MSBs), which have recently been found to be a major component of experience-related neocortical plasticity, and synapses with perforated postsynaptic densities (PSDs), which are putatively associated with enhanced synaptic efficacy. In comparison with sham-operated rats, there was an increase in the proportion and ratio of synapses to neurons formed by MSBs and in synapses with perforated PSDs at 30 days after the lesions. Furthermore, perforated synapses formed by MSBs were markedly increased at 18 and 30 days after the lesion in comparison with sham-operated rats. Preceding these synaptic structural changes (at 10 days postlesion), myelinated axons were reduced in volume fraction and volume per neuron in comparison with sham-operated rats but returned to normal levels at subsequent time points. These results are consistent with a lesion-induced degeneration and subsequent sprouting of axons. Together, these data indicate that a major restructuring of synaptic connectivity occurs in the cortex opposite FLsmc lesions in adult animals. This lesion-induced restructuring may be guided by ongoing changes in the use of the forelimbs.     

Recovery from medial prefrontal cortex injury during adolescence: implications for age-dependent plasticity

Focal cortical injuries generate various behavioral deficits associated with different morphological changes. The age and the area of the injury determine the nature and extent of recovery represented by the level of performance in various behavioral tasks. Previously, we have shown that motor cortex injury in early (but not late) adolescence leads to behavioral deficits that do not recover spontaneously with time. Considering the fact that the pace of brain maturation differs in different brain areas, we undertook to examine the pattern of spontaneous recovery following medial prefrontal cortex (mPFC) lesion in early or late adolescence. A battery of motor tasks (postural asymmetry, skilled reaching, sunflower seed manipulation, forepaw inhibition in swimming) was used to investigate the pattern of behavioral recovery following mPFC lesions. Golgi-Cox analysis was used to examine dendritic reorganization of the relevant brain areas. The results indicated that rats perform poorly when receiving mPFC injuries in late adolescence in contrast to when they receive the lesion in early adolescence. Almost opposite pattern of recovery following motor cortex and medial prefrontal injuries in early and late adolescence will be discussed as an age-area dependent model for prognosis of brain injury during adolescence.     

Intracerebroventricular administration of growth hormone induces morphological changes in pyramidal neurons of the hippocampus and prefrontal cortex in adult rats

A growing body of evidence suggests that growth hormone (GH) affects synaptic plasticity at both the molecular and electrophysiological levels. However, unclear is whether plasticity that is stimulated by GH is associated with changes in neuron structure. This study investigated the effect of intracerebroventricular (ICV) administration of GH on the morphology of pyramidal neurons of the CA1 region of the dorsal hippocampus and layer III of the prefrontal cortex. Male Wistar rats received daily ICV injections of GH (120 ng) for 7 days, and they were euthanized 21 days later. Changes in neuronal morphology were evaluated using Golgi‐Cox staining and subsequent Sholl analysis. GH administration increased total dendritic length in the CA1 region of the dorsal hippocampus and prefrontal cortex. The Sholl analysis revealed an increase in dendritic length of the third to eighth branch orders in the hippocampus and from the third to sixth branch orders in the prefrontal cortex. Interestingly, GH treatment increased the density of dendritic spines in both brain regions, favoring the presence of mushroom‐like spines only in the CA1 hippocampal region. Our results indicated that GH induces changes in the length of dendritic trees and the density of dendritic spines in two high‐plasticity brain regions, suggesting that GH‐induced synaptic plasticity at the molecular and electrophysiological levels may be associated with these structural changes in neurons.     

Motor cortical stimulation promotes synaptic plasticity and behavioral improvements following sensorimotor cortex lesions

Cortical stimulation (CS) as a means to modulate regional activity and excitability in cortex is emerging as a promising approach for facilitating rehabilitative interventions after brain damage, including stroke. In this study, we investigated whether CS-induced functional improvements are linked with synaptic plasticity in peri-infarct cortex and vary with the severity of impairments. Adult rats that were proficient in skilled reaching received subtotal unilateral ischemic sensorimotor cortex (SMC) lesions and implantation of chronic epidural electrodes over remaining motor cortex. Based on the initial magnitude of reaching deficits, rats were divided into severely and moderately impaired subgroups. Beginning two weeks post-surgery, rats received 100 Hz cathodal CS at 50% of movement thresholds or no-stimulation control procedures (NoCS) during 18 days of rehabilitative training on a reaching task. Stereological electron microscopy methods were used to quantify axodendritic synapse subtypes in motor cortical layer V underlying the electrode. In moderately, but not severely impaired rats, CS significantly enhanced recovery of reaching success. Sensitive movement analyses revealed that CS partially normalized reaching movements in both impairment subgroups compared to NoCS. Additionally, both CS subgroups had significantly greater density of axodendritic synapses and moderately impaired CS rats had increases in presumed efficacious synapse subtypes (perforated and multiple synapses) in stimulated cortex compared to NoCS. Synaptic density was positively correlated with post-rehabilitation reaching success. In addition to providing further support that CS can promote functional recovery, these findings suggest that CS-induced functional improvements may be mediated by synaptic structural plasticity in stimulated cortex.     

Nerve growth factor stimulates growth of cortical pyramidal neurons in young adult rats

The cytoarchitectonics of pyramidal neurons in the cerebral cortex of non-lesioned rats can be re-modeled by i.c.v. infusions of nerve growth factor (NGF). 4 months after the application of NGF, the pyramidal neurons in layers III and V of the motor cortex and layer V of the anterior cingulate cortex were analyzed and compared with pyramidal neurons from vehicle-treated rats. NGF-treated brains showed: (1) significant increase in dendritic branching in the basilar fields of the layer V, but not layer III, neurons; and (2) a significant increase in spine density in the terminal, but not proximal, dendritic branches. These findings indicated that, besides its known effects on forebrain cholinergic neurons, NGF produces a very generalized synaptic re-modeling involving the cells responsible for the major output of the cerebral cortex in the intact adult brain. © 1979 Elsevier Science B.V. All rights reserved.     

Calcium-induced long-term potentiation in horizontal connections of rat motor cortex

A transient (10 min) exposure of brain slices of young adult rats to elevated extracellular calcium (5 mM) resulted in a long-lasting potentiation of field potentials evoked in layer II/III and layer V horizontal connections of the primary motor cortex. This form of synaptic plasticity was blocked by D,L-2-amino-5-phosphonovalerate (APV, 100 micro M), an antagonist of NMDA receptors.     

The problem of relating plasticity and skilled reaching after motor cortex stroke in the rat

The plasticity of the nervous system is illustrated in the many new neuronal connections that are formed during the acquisition of behavioral skills, loss of function after brain injury, and subsequent recovery of function. The present review describes the acquisition of skilled reaching, the act of reaching for food with a forelimb, and the changes that take place in skilled reaching following motor cortex stroke. The review then discusses the difficulty in associating plastic changes with specific aspects of behavioral change. Skilled reaching behavior is complex and consists of a number of oppositions (stimulus response relationships), between the rat and the food target, a number of forelimb gestures (non-weight supporting movements), which are performed to obtain food, and a complex series of segmental movements (of the limb, head, and trunk), all of which influence the success of the act. Measures of these four aspects of skilled reaching behavior following motor cortex stroke reveal that there are a number of learned changes that take place at different times, including learned nonuse, learned bad-use, and forgetting. The widespread dendritic proliferation, axonal growth, and synaptic formation that take place both before and after stroke are difficult to precisely relate to these behavioral changes. Whereas plasticity is usually proposed to be associated with improved performance it is suggested that future work should attempt to better relate plastic changes to the details of behavioral changes.     

Widespread but regionally specific effects of experimenter- versus self-administered morphine on dendritic spines in the nucleus accumbens,hippocampus, and neocortex of adult rats

We studied the effects of self-administered (SA) vs. experimenter-administered (EA) morphine on dendritic spines in the hippocampal formation (CA1 and dentate), nucleus accumbens shell (NAcc-s), sensory cortex (Par1 and Oc1), medial frontal cortex (Cg3), and orbital frontal cortex (AID) of rats. Animals in the SA group self-administered morphine in 2-h sessions (0.5 mg/kg/infusion, i.v.) for an average of 22 sessions and animals in the EA group were given daily i.v. injections of doses that approximated the total session dose for matched rats in Group SA (average cumulative dose/session of 7.7 mg/kg). Control rats were given daily i.v. infusions of saline. One month after the last treatment the brains were processed for Golgi-Cox staining. In most brain regions (Cg3, Oc1, NAcc-s) morphine decreased the density of dendritic spines, regardless of mode of administration (although to a significantly greater extent in Group SA). However, only SA morphine decreased spine density in the hippocampal formation and only EA morphine decreased spine density in Par1. Interestingly, in the orbital frontal cortex morphine significantly increased spine density in both Groups SA and EA, although to a much greater extent in Group SA. We conclude: 1) Morphine has persistent (at least 1 month) effects on the density of dendritic spines in many brain regions, and on many different types of cells (medium spiny neurons, pyramidal cells, and granule cells); 2) The effect of morphine on spine density (and presumably synaptic organization) varies as a function of both brain region and mode of drug administration; and 3) The ability of morphine to remodel synaptic inputs in a regionally specific manner may account for the many different long-term sequelae associated with opioid use.