Grazyna Gorny

Cocaine self-administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens and neocortex.

We studied the influence of cocaine use on the structure of neurons in brain regions that contribute to its rewarding effects by allowing rats to self‐administer cocaine (0.33 mg/infusion) for 1 h a day for 1 month. Control animals were left undisturbed or allowed to work for food for the same period of time. After an additional 1 month drug‐free period the brains were processed for Golgi‐Cox staining. In rats that self‐administered cocaine, but not rats that worked for food, there was a significant increase in dendritic branching and in the density of dendritic spines on medium spiny neurons in the shell of the nucleus accumbens and on pyramidal cells in the prefrontal and parietal (but not occipital) cortex. There was also a 2.6‐fold increase in the incidence of spines with multiple heads (branched spines) on medium spiny neurons. Finally, in the prefrontal cortex some of the apical dendrites of pyramidal cells appeared misshaped, having large bulbous structures on their terminal tips. We speculate that cocaine self‐administration experience alters patterns of synaptic connectivity within limbocortical circuitry that is thought to contribute to cocaines incentive motivational effects and may have neuropathological effects in frontal areas involved in decision making and judgment. Together, these two classes of drug‐induced neuroadaptations may contribute to the development of addiction. Synapse 39:257–266, 2001.

Age, experience and the changing brain.

In this review, various aspects of how environmental experience effects the structure of the cortex at different times in the age of the animal are summarized. The interactions of brain injury and sex on the age-dependent plastic changes in the cortex are also considered. Finally, we have attempted to reach some general conclusions that describe the effects of age, experience, sex, and injury on the cortex.

Neural and Behavioral Plasticity Associated with the Transition from Controlled to Escalated Cocaine Use

BACKGROUND Rats given extended access to cocaine develop several symptoms of addiction, including a gradual escalation of drug intake, whereas rats given limited access do not. We asked here whether extended access to cocaine also produces drug-induced sensitization, a form of neurobehavioral plasticity implicated in addiction. METHODS Rats were given limited (1 hour/session) or extended access (6 hours/session) to self-administered cocaine. Following a period of abstinence, rats were selected at random for assessment of their psychomotor response to cocaine or drug-seeking during extinction or for anatomic studies. RESULTS When re-exposed to cocaine, rats allowed extended drug access showed greater drug-seeking behavior and were hypersensitive (sensitized) to the psychomotor activating effects of cocaine compared with rats given limited access. Extended access to cocaine was also associated with a greater increase in the density of dendritic spines on neurons specifically in the core of the nucleus accumbens (and not in the shell or medial or orbital frontal cortex). CONCLUSIONS The transition from stable to escalated cocaine use, a hallmark of addiction, is associated with especially robust behavioral sensitization and synaptic reorganization in the core of the nucleus accumbens.

Amphetamine or cocaine limits the ability of later experience to promote structural plasticity in the neocortex and nucleus accumbens

Drugs of abuse and many other kinds of experiences share the ability to alter the morphology of neuronal dendrites and spines, the primary site of excitatory synapses in the brain. We hypothesized, therefore, that exposure to psychostimulant drugs might influence later experience-dependent structural plasticity. We tested this hypothesis by treating rats repeatedly with amphetamine or cocaine and then housing them in either a complex environment or standard laboratory cages for 3-3.5 mo. The brains were processed for Golgi-Cox staining, and the number of dendritic branches and the density of dendritic spines on medium spiny neurons in the nucleus accumbens and pyramidal cells in the parietal cortex were quantified. On most measures, prior treatment with amphetamine or cocaine interfered with the ability of experience in a complex environment to increase dendritic arborization and spine density. We conclude that in some brain regions, repeated exposure to psychomotor-stimulant drugs limits the ability of later experience to produce this form of synaptic plasticity, which may contribute to the persistent behavioral and cognitive deficits associated with drug abuse.

Experience-dependent changes in dendritic arbor and spine density in neocortex vary qualitatively with age and sex.

Male and female Long-Evans hooded rats were placed in the complex environments for 3 months either at weaning (22 days), in young adulthood (120 days), or in senescence (24 months). The dendritic morphology of both the apical and basilar fields of layer III pyramidal cells was analyzed in both parietal and visual cortex. There were two novel results. First, although spine density was increased significantly with complex-housing in adulthood, it was decreased significantly by the same housing during development. Second, dendritic length was increased in both parietal and occipital cortex at all ages in males and was increased in adult females as well, but juvenile females showed no change in dendritic length in the occipital cortex and only a small effect on the apical field in parietal cortex. Thus, there are qualitative differences in the changes in spine density at different ages and the dendritic changes in response to complex versus isolated housing vary with sex, and in females, the changes vary with age as well. These results may explain some of the apparent inconsistencies in reports of spine and dendrite changes in the literature.

Cortical Plasticity and the Development of Behavior After Early Frontal Cortical Injury

It has been known for over 100 years that frontal lobe injury in children is often associated with considerably more functional recovery than after similar injury in adulthood. Systematic study of frontal cortical injury in laboratory animals has shown that this recovery is tightly tied to developmental age: There is a brief window of time during cortical development during which the brain is able to compensate. Simply being young is not sufficient because injury prior to this critical period leads to miserable behavioral outcomes. For humans, the least favorable time for cortical injury is likely at the end of the gestational period, perhaps including the 1st month or so of life whereas the most favorable time is around 1 to 2 years of age. In addition to age, the extent of behavioral recovery is influenced by age at assessment, the nature of the behavioral assessment, sex, and lesion size. Anatomical studies have shown that functional recovery following early cortical injury is correlated with a reorganization of remaining cortical circuitry, including increased dendritic arborization and increased spine density. Recovery, and the compensatory anatomical changes, can also be potentiated by application of different treatments including behavioral therapy, trophic factors, and neuromodulators. Finally, there is preliminary evidence in laboratory animals to suggest that it may be possible to induce neural regeneration in the injured brain and that the regenerated brain functions to support functional recovery.

Progressive atrophy of pyramidal neuron dendrites in autoimmune MRL-lpr mice

The autoimmune-prone MRL-lpr substrain of mice develop an autoimmunity-associated behavioral syndrome (AABS) which resembles in many respects the behavior of animals exposed to chronic stress. The present study examined whether these mice show changes in the morphology of neuronal dendrites, as found in animals exposed to chronic stress. A modified Golgi-Cox procedure was used to visualize the dendrites of pyramidal neurons in the parietal cortex and in the CA1 hippocampal field of 5-week and 14-week old MRL-lpr mice and MRL + / + controls. Reduced dendritic branching and length, and an up to 20% loss of dendritic spines were observed in parietal and hippocampal pyramidal neurons of MRL-lpr mice at both ages. In the parietal cortex, there was an age-dependent potentiation in the reduction of basilar, but not apical, dendrite branching and length, as well as in the loss of spines on basilar segments. Loss of spines in the hippocampus followed an age-related course for apical but not basilar dendrites. Moreover, compared to age-matched controls, brain weight was smaller in MRL-lpr mice at 14 but not 5 weeks of age. Considering that dendritic atrophy becomes more extensive when autoimmune disease is florid in MRL-lpr mice, it is proposed that immune/inflammatory factor(s) produce dendritic loss. Reduced dendritic complexity may represent, at least in part, a structural basis for the altered behavioral profile of MRL-lpr mice.

Possible regeneration of rat medial frontal cortex following neonatal frontal lesions

The experiments described here show that the cavity left by midline frontal cortex removals at 10 days of age (P10) fills in with neural tissue. Similar changes are not found at earlier and later ages. This neuronal filling is blocked by prior pretreatment by administration of Bromodeoxyuridine (BrdU) on embryonic day 13. Administration of BrdU following the P10 lesion does not interfere with regrowth. Subsequent immunohistochemical staining for BrdU demonstrates the regrown area to be composed of newly generated cells. which include pyramidal and nonpyramidal neurons. Injections of a retrograde tracer into the striatum or posterior parietal cortex shows that the new neurons have connections similar to those of undamaged brains. The regrowth of this tissue is correlated with recovery of function in a test of forelimb use. Thus, the mammalian brain, during some privileged postnatal stages of growth. is capable of extensive reorganization that includes regeneration of lost neurons. These results are discussed in relation to the proximity of the lesion to the stem cells in the lateral ventricle and their postnatal migrational activities.

Immunosuppression prevents neuronal atrophy in lupus-prone mice: evidence for brain damage induced by autoimmune disease?

An early onset of systemic, lupus-like disease in MRL-lpr mice is accompanied by deterioration in their behavioral performance and atrophy of pyramidal neurons in the parietal cortex and the hippocampal CA1 area. Using the immunosuppressive drug cyclophosphamide (CY) to attenuate the disease, we have tested the hypothesis that the autoimmune/inflammatory process is responsible for changes in brain morphology. A modified Golgi impregnation method revealed that, in comparison to saline-treated controls, immunosuppressive treatment with CY (100 mg/kg/week i.p. over 8 weeks) increased dendritic branching and spine numerical density in the CA1 region of MRL-lpr mice and MRL +/+ mice, which develop less severe manifestations of the disease. More interestingly, CY selectively prevented the atrophy and aberrant morphology of pyramidal neurons in the parietal cortex of MRL-lpr mice. The neuropathological measures (in particular reduced dendritic spine density) significantly correlated with increased serum levels of antinuclear antibodies and splenomegaly. The present results support the hypothesis that chronic autoimmune disease induces functionally important changes in neuronal morphology, and provide an empirical basis for understanding the behavioral dysfunction in systemic lupus erythematosus and autoimmune phenomena reported in some forms of mental illness.

Amphetamine-Induced Changes in Dendritic Morphology in Rat Forebrain Correspond to Associative Drug Conditioning Rather than Nonassociative Drug Sensitization

BACKGROUND Systemic exposure to amphetamine (AMPH) leads to a number of long-lasting neuroadaptations including changes in dendritic morphology in rat forebrain. It remains unknown whether these changes relate to associative drug conditioning or to nonassociative drug sensitization, two forms of plasticity produced by systemic exposure to AMPH. METHODS We compared the behavioral, neuronal, and morphologic consequences of exposing rats to intraperitoneal (IP) AMPH to those of exposure to AMPH applied to the ventral tegmental area (VTA), infusions that sensitize AMPH-induced locomotion and nucleus accumbens (NAcc) DA overflow but do not produce drug conditioning. RESULTS Both IP and VTA AMPH exposure sensitized locomotion and NAcc DA overflow, but only IP AMPH exposure produced conditioned locomotion. Importantly, whereas IP AMPH exposure increased spine density and dendritic length and branching in the NAcc, exposure to VTA AMPH produced the opposite effects. A similar differentiation of effects was observed in cortical areas. CONCLUSIONS Together these findings suggest that the morphological changes seen following IP AMPH exposure reflect associative drug conditioning rather than nonassociative drug sensitization. The decreases observed in the NAcc of VTA AMPH exposed rats may reflect the inability of these infusions to support conditioning.