Biomedical subjects

Cara L Wellman

Publications and source records attributed to Cara L Wellman.

12 recordsLinked to original sources

PubMed2006

Receptor autoradiographic correlates of deafferentation-induced reorganization in adult primate somatosensory cortex.

The primate somatosensory system provides an excellent model system with which to investigate adult neural plasticity. We have previously shown that transection of the median and ulnar nerves is followed by an expansion in the representation of radial nerve skin, and that this plasticity proceeds in stages. Immediately following nerve injury, new receptive fields are "unmasked" in a fraction of the affected cortex. The remaining deprived cortex regains responsiveness to tactile stimulation over the following days to weeks. Given these progressive changes, it has been suggested that different mechanisms might account for the earlier and later phases of reorganization. In the present experiments, we quantified receptor autoradiographic binding data for GABAA and GABAB, AMPA, and NMDA receptors in the primary somatosensory cortices of adult squirrel monkeys at four postnerve injury survival durations: immediately (1-3 hours), 3 days, 1 month, and 2 months. We found dramatic reductions in GABAA binding in layer IV within hours following nerve injury, and this reduction was maintained across all survival durations. This finding is consistent with the idea that the earliest reorganizational changes are due to a relaxation in tonic inhibitory mechanisms permitting the expression of formerly subthreshold receptive fields. GABAB receptor binding is decreased in layer IV by 1 month after nerve injury, while binding for AMPA receptors is increased in layer IV by this time. These findings are consistent with our previous suggestion that the second stage of reorganization proceeds via mechanisms comparable to those revealed to account for NMDA-dependent long-term potentiation in the hippocampus.

Afferent Pathways↗

PubMed2006

Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice.

Extinction of conditioned fear responses is an active learning process resulting from the repeated presentation of a conditioned stimulus in the absence of the unconditioned aversive stimulus. Recent research implicates the medial prefrontal cortex (mPFC) in the mediation of fear extinction in rodents and the pathophysiology of posttraumatic stress disorder. However, there is currently little understanding of precisely how stress can impact fear extinction and the neural circuitry subserving this behavior. The present study examined the effects of brief exposure to an uncontrollable stressor on (1) fear conditioning and fear extinction, and (2) dendritic morphology of pyramidal neurons in the infralimbic (IL) and prelimbic (PL) regions of the mPFC in mice. Exposure to three episodes of stress ending 24 h before fear conditioning significantly attenuated the rate of cued fear extinction relative to nonstressed controls, but did not affect fear conditioning or cue or context recall. Analysis of Golgi-stained neurons showed that one or three exposures to daily swim stress caused significant retraction of terminal branches of apical, but not basilar, dendrites of IL neurons. In contrast, PL neuronal morphology was unaltered by stress. These data demonstrate that IL, but not PL, neurons are highly sensitive to even brief exposure to stress, and that this same form of stress impairs fear extinction. Present findings suggest that trauma may compromise the functional integrity of the mPFC with implications for the pathophysiology of certain neuropsychiatric disorders.

Animals↗

PubMed2005

Chronic stress impairs recall of extinction of conditioned fear.

Chronic restraint stress produces retraction of apical dendrites of pyramidal neurons in medial prefrontal cortex. To begin to examine the functional significance of this dendritic reorganization, we assessed the effects of chronic restraint stress on a prefrontally mediated behavior, extinction of conditioned fear. After bar press training to obtain a baseline of activity against which to measure freezing, rats were either unstressed or stressed via placement in a plastic restrainer (3 h/day for 1 week). After an additional day of bar press training, rats underwent fear conditioning and extinction. Rats received five habituation trials to a 30-s tone (4.5 kHz, 80 db) followed by seven pairings of tone and footshock (500 ms, 0.5 mA). One hour later, rats received tone-alone extinction trials to criterion. The next day, rats received 15 additional extinction trials. Percent freezing was assessed during all phases of training. Stress did not significantly affect unconditioned responding to tone, acquisition of conditioned fear, or initial extinction, but significantly increased freezing on extinction day 2. Thus, consistent with the regressive dendritic changes seen in medial prefrontal cortex, one week of restraint stress specifically impaired recall of extinction, a pattern of deficits typical of animals with impaired medial prefrontal function.

Animals↗

PubMed2005

Differential environmental exposure alters NMDA but not AMPA receptor subunit expression in nucleus accumbens core and shell.

Environmentally enriched (EE) rats show neurobehavioral differences relative to less stimulated, socially isolated (SI) littermates. Although experience-dependent cortical changes are presumed to underlie learning differences in these differentially housed animals, EE rats show reduced reward-seeking behavior and altered cytoarchitecture and dopaminergic function in the nucleus accumbens (NAcc), a brain area involved in adaptive, goal-directed activity. Given that glutamate and its interaction with dopamine regulate motivational and associative processing in this brain region, we assessed expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and the GluR1 subunit of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor in the NAcc core and shell of EE and SI rats. Our results indicate fewer intensely stained NR1 immunopositive neurons in both core and shell of EE relative to SI rats. No such differences were observed in GluR1 staining. These results suggest that environmental experience alters NMDA but not AMPA receptor expression in NAcc. Increased expression of the NR1 subunit in the NAcc of SI rats may augment impulsivity and reward-seeking behavior relative to EE rats.

Animals↗

PubMed2005

Mild, short-term stress alters dendritic morphology in rat medial prefrontal cortex.

Prefrontal cortex is a target for glucocorticoids, shows neurochemical changes in response to stress and mediates many of the behaviors that are altered by chronic corticosterone administration. Three weeks of either daily corticosterone injections or 3 h daily restraint stress result in dendritic changes in pyramidal neurons in medial prefrontal cortex. Interestingly, vehicle injection results in similar but less pronounced changes. Thus, the mild stress of daily injections alone may alter morphology of medial prefrontal cortex, suggesting an exquisite sensitivity to chronic stress. To further examine this morphological sensitivity, we assessed the effect of 1 week of daily brief restraint stress on dendritic morphology in medial prefrontal cortex. Male rats were restrained 10 min per day for one week, handled daily or left unhandled. Rats were then overdosed and brains were stained using a Golgi-Cox procedure. Layer II-III pyramidal neurons in medial prefrontal cortex were drawn and dendritic morphology was quantified. One week of daily brief restraint resulted in selective remodeling of apical dendrites, with atrophy of up to 22-35% in distal branches and sparing of proximal branches. This pattern of reorganization is similar to that seen after either corticosterone injections or 3 weeks of daily 3 h restraint stress. Thus, the stress-induced dendritic changes in medial prefrontal cortex occur rapidly, and in response to a mild stressor.

Adaptation, Physiological↗

PubMed2004

Aging and cholinergic deafferentation alter GluR1 expression in rat frontal cortex.

Previously, we demonstrated that plasticity of frontal cortex is altered in aging rats: lesions of the nucleus basalis magnocellularis (NBM) produce larger declines in dendritic morphology in frontal cortex of aged rats compared to young adults. Cholinergic afferents from the NBM modulate glutamatergic transmission in neocortex, and glutamate is known to be involved in dendritic plasticity. To begin to identify possible mechanisms underlying age-related differences in plasticity after NBM lesion, we assessed the effect of cholinergic deafferentation on expression of the AMPA receptor subunit GluR1 in frontal cortex of young adult and aging rats. Young adult, middle-aged, and aged rats received sham or 192 IgG-saporin lesions of the NBM, and an unbiased stereological technique was used to estimate the total number of intensely GluR1-immunopositive neurons in layer II-III of frontal cortex. While the number of GluR1-positive neurons was increased in both middle-aged and aged rats, lesions markedly increased the number of intensely GluR1-immunopositive neurons in frontal cortex of young adult rats only. This age-related difference in lesion-induced expression of AMPA receptor subunit protein could underlie the age-related differences in dendritic plasticity after NBM lesions.

Acetylcholinesterase↗

PubMed2004

Morphological correlates of injury-induced reorganization in primate somatosensory cortex.

BACKGROUND: Topographic reorganization of central maps following peripheral nerve injury has been well characterized. Despite extensive documentation of these physiological changes, the underlying anatomical correlates have yet to be fully explored. In this study, we used Golgi impregnation and light microscopy to assess dendritic morphology following denervation of the glabrous hand surface in adult primates. RESULTS: After survival durations that permit complete physiologically-defined reorganization, we find a systematic change in the dendritic arborization pattern of both layer II/III pyramidal and layer IV spiny stellate cells in the contralateral hand region of area 3b, compared to unaffected cortical areas. In general, our analyses indicate a progressive expansion of distal regions of the dendritic arbor with no appreciable changes proximally. This pattern of distal dendritic elaboration occurs for both basilar and apical dendrites. CONCLUSIONS: These observations are consistent with the notion that latent inputs gain expression in reorganized cortex after nerve injury via their influence through contacts with more distally located termination sites.

Animals↗

PubMed2004

Chronic stress alters dendritic morphology in rat medial prefrontal cortex.

Chronic stress produces deficits in cognition accompanied by alterations in neural chemistry and morphology. Medial prefrontal cortex is a target for glucocorticoids involved in the stress response. We have previously demonstrated that 3 weeks of daily corticosterone injections result in dendritic reorganization in pyramidal neurons in layer II-III of medial prefrontal cortex. To determine if similar morphological changes occur in response to chronic stress, we assessed the effects of daily restraint stress on dendritic morphology in medial prefrontal cortex. Male rats were exposed to either 3 h of restraint stress daily for 3 weeks or left unhandled except for weighing during this period. On the last day of restraint, animals were overdosed and brains were stained using a Golgi-Cox procedure. Pyramidal neurons in lamina II-III of medial prefrontal cortex were drawn in three dimensions, and the morphology of apical and basilar arbors was quantified. Sholl analyses demonstrated a significant alteration of apical dendrites in stressed animals: overall, the number and length of apical dendritic branches was reduced by 18 and 32%, respectively. The reduction in apical dendritic arbor was restricted to distal and higher-order branches, and may reflect atrophy of terminal branches: terminal branch number and length were reduced by 19 and 35%. On the other hand, basilar dendrites were not affected. This pattern of dendritic reorganization is similar to that seen after daily corticosterone injections. This reorganization likely reflects functional changes in prefrontal cortex and may contribute to stress-induced changes in cognition.

Animals↗

PubMed2004

Age-dependent effect of cholinergic lesion on dendritic morphology in rat frontal cortex.

Previously, we demonstrated that plasticity of frontal cortex is altered in aging rats: 3 months after surgery, excitotoxic lesions of the nucleus basalis magnocellularis (NBM) produce larger declines in dendritic morphology in frontal cortex of aged rats relative to young adults. To determine whether the differential effect of the lesion was due specifically to loss of cholinergic input from the NBM, we assessed dendritic morphology in frontal cortex after specific cholinergic depletion in young adult, middle-aged, and aged male rats. Rats received unilateral sham or 192-IgG-saporin lesions of the NBM. Two weeks after surgery, brains were stained using a Golgi-Cox procedure. Dendritic morphology was quantified in pyramidal neurons in layers II-III of frontal cortex. Although lesions altered apical dendrites at all ages, these effects were most pronounced in aged rats. In addition, lesions produced marked atrophy of basilar dendrites in middle-aged and aged rats only. Thus, the differential dendritic atrophy resulting from NBM lesions in aged rats occurs within 2 weeks after lesion, and results specifically from loss of cholinergic innervation.

Aging↗

PubMed2003

Differential effects of cholinergic lesions on dendritic spines in frontal cortex of young adult and aging rats.

Previously, we demonstrated that plasticity of frontal cortex is altered in aging rats: cholinergic lesions of the nucleus basalis magnocellularis (NBM) produce larger declines in dendritic morphology in frontal cortex of middle-aged and aged rats relative to young adults. To more closely examine the interactive effects of age and cholinergic deafferentation on synaptic connectivity in frontal cortex, we assessed the effects of specific cholinergic lesions on spine density of frontal cortical neurons in young adult, middle-aged, and aged rats. Rats received unilateral sham or 192 IgG-saporin lesions of the NBM. Two weeks after surgery, brains were stained using a Golgi-Cox procedure, and spine density was quantified in second-, third-, and fourth-order basilar dendrites of pyramidal neurons in layer II-III of frontal cortex. Spine density was reduced at all branch orders in aged, sham-lesioned rats. In addition, whereas lesions produced a marked increase in spine density on second- and third-order branches in young adult rats, lesions failed to significantly alter spine density in middle-aged and aged rats. Thus, the upregulation of dendritic spines may be a compensatory response to deafferentation, which is lost with advancing age.

Aging↗

PubMed2003

Daily injections alter spine density in rat medial prefrontal cortex.

Apical dendrites of pyramidal neurons in medial prefrontal cortex are reorganized after chronic corticosterone treatment. In this study, we assessed the effects of chronic corticosterone administration on dendritic spines. Adult male rats received sc injections of either corticosterone or vehicle daily for 3 weeks or were left untreated. Layer II-III neurons in medial prefrontal cortex were stained using a Golgi-Cox procedure and spines were counted on the portions of apical dendrites where maximal corticosterone-induced dendritic changes occur. In vehicle- and corticosterone-treated rats, spine density proximal to the soma was increased relative to untreated rats, while spine density in the distal portion of the apical arbor was unchanged, suggesting that daily handling alone altered spine density. This stress-induced change in spine density likely reflects important functional changes in excitatory synaptic inputs in prefrontal cortex.

Animals↗

PubMedDate not supplied

NMDA receptor binding declines differentially in three spinal motor nuclei during postnatal development.

The NMDA subtype of glutamate receptors mediates a variety of neuronal processes involved in the development of dendritic morphology. For example, NMDA receptor antagonism during the early postnatal period attenuates dendritic growth in spinal motoneurons. NMDA receptors are present in high levels in the spinal cord early in the postnatal period and decline during development, a period of extensive dendritic plasticity in the spinal cord. Previous studies have suggested that an adult pattern of distribution of NMDA receptors is established as early as postnatal day (P)21 (day of birth = P1). However, given that dendritic growth in spinal motoneurons is not complete by this age and that NMDA receptor activation is necessary for dendritic growth, we assessed NMDA receptor binding in specific spinal motor nuclei during normal development. NMDA receptors were labeled with [3H]MK-801 at P7, P14, P28, P49, and in adult male rats. Receptor binding in the spinal nucleus of the bulbocavernosus (SNB), dorsolateral nucleus (DLN) and retrodorsolateral nucleus (RDLN) was measured using in vitro quantitative autoradiography. NMDA receptor binding over the SNB, DLN and RDLN in intact males was initially high, and declined to adult levels. However, the time course of the decline differed across nuclei. The local decline in NMDA receptor binding observed in the SNB and DLN is coincident with the periods of dendritic growth in these nuclei, further supporting a role for NMDA receptors in the development of motoneuron dendritic morphology.

Age Factors↗