Showing papers by "Javier DeFelipe published in 2003"

Alterations of Neocortical Pyramidal Cell Phenotype in the Ts65Dn Mouse Model of Down Syndrome: Effects of Environmental Enrichment

Abstract: Mental retardation in individuals with Down syndrome (DS) is thought to result from anomalous development and function of the brain; however, the underlying neuropathological processes have yet to be determined. Early implementation of special care programs result in limited, and temporary, cognitive improvements in DS individuals. In the present study, we investigated the possible neural correlates of these limited improvements. More specifically, we studied cortical pyramidal cells in the frontal cortex of Ts65Dn mice, a partial trisomy of murine chromosome 16 (MMU16) model characterized by cognitive deficits, hyperactivity, behavioral disruption and reduced attention levels similar to those observed in DS, and their control littermates. Animals were raised either in a standard or in an enriched environment. Environmental enrichment had a marked effect on pyramidal cell structure in control animals. Pyramidal cells in environmentally enriched control animals were significantly more branched and more spinous than non-enriched controls. However, environmental enrichment had little effect on pyramidal cell structure in Ts65Dn mice. As each dendritic spine receives at least one excitatory input, differences in the number of spines found in the dendritic arbors of pyramidal cells in the two groups reflect differences in the number of excitatory inputs they receive and, consequently, complexity in cortical circuitry. The present results suggest that behavioral deficits demonstrated in the Ts65Dn model could be attributed to abnormal circuit development.

Lack of thyroid hormone receptor alpha1 is associated with selective alterations in behavior and hippocampal circuits.

Abstract: Brain development and function are dependent on thyroid hormone (T3), which acts through nuclear hormone receptors. T3 receptors (TRs) are transcription factors that activate or suppress target gene expression in a hormone-dependent or -independent fashion. Two distinct genes, TRalpha and TRbeta, encode several receptor isoforms with specific functions defined in many tissues but not in the brain. Mutations in the TRbeta gene cause the syndrome of peripheral resistance to thyroid hormone; however, no alterations of the TRalpha gene have been described in humans. Here we demonstrate that mice lacking the TRalpha1 isoform display behavioral abnormalities of hippocampal origin, as shown by the open field and fear conditioning tests. In the open field test mutant mice revealed less exploratory behavior than wild-type mice. In the contextual fear conditioning test mutant mice showed a significantly higher freezing response than wild-type controls when tested 1 week after training. These findings correlated with fewer GABAergic terminals on the CA1 pyramidal neurons in the mutant mice. Our results indicate that TRalpha1 is involved in the regulation of hippocampal structure and function, and raise the possibility that deletions or mutations of this receptor isoform may lead to behavioral changes or even psychiatric syndromes in humans.

Different populations of tyrosine-hydroxylase-immunoreactive neurons defined by differential expression of nitric oxide synthase in the human temporal cortex.

Abstract: In the mammalian neocortex, neurons containing tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, constitute an enigmatic and ill-defined group of aspiny non-pyramidal cells. In the human neocortex, these neurons are mostly found in layers V-VI, the same layers in which another conspicuous group of nitrergic non-pyramidal cells are found - those containing nitric oxide synthase (nNOS) and that can be labeled by nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) histochemistry. The main aim of the present study was to determine the extent to which neurons and fibers containing TH, NADPHd or nNOS co-localize in the human temporal cortex, using immunocytochemistry and NADPHd histochemistry. Furthermore, we have quantified the degree to which axons immunoreactive (ir) for TH contact the somata of neurons by co-labeling with the neuron-specific nuclear protein NeuN. As a result, we show that the population of TH-ir neurons can be subdivided into two main neurochemical groups: those expressing nNOS (26%) and those that do not (74%). There was no co-localization of TH with nNOS in the prominent horizontally oriented plexus of fibers in layer I and we did not observe any double bouquet cells, chandelier cells or basket cells that contained TH. Finally, we observed that only 6% of the TH-ir axonal boutons examined (n = 1724) could be seen to contact neuronal somata. Thus, most TH-ir axons must form synapses with dendrites. In conjunction with data from previous studies, these results suggest that TH is found in different neurochemically defined subpopulations of non-pyramidal neurons in layers V-VI of the human temporal cortex. Consequently, it appears that a partial overlap of the catecholaminergic and nitrergic systems is probably due to the intrinsic cortical TH-nNOS-ir neurons.

Motor System Development Depends on Experience: A Microgravity Study of Rats

Abstract: Animals move about their environment by sensing their surroundings and making adjustments according to need. All animals take the force of gravity into account when the brain and spinal cord undertake the planning and execution of movements. To what extent must animals learn to factor in the force of gravity when making neural calculations about movement? Are animals born knowing how to respond to gravity, or must the young nervous system learn to enter gravity into the equation? To study this issue, young rats were reared in two different gravitational environments (the one-G of Earth and the microgravity of low Earth orbit) that necessitated two different types of motor operations (movements) for optimal behavior. We inquired whether those portions of the young nervous system involved in movement, the motor system, can adapt to different gravitational levels and, if so, the cellular basis for this phenomenon. We studied two groups of rats that had been raised for 16 days in microgravity (eight or 14 days old at launch) and compared their walking and righting (ability to go from upside down to upright) and brain structure to those of control rats that developed on Earth. Flight rats were easily distinguished from the age-matched ground control rats in terms of both motor function and central nervous system structure. Mature surface righting predominated in control rats on the day of landing (R+O), while immature righting predominated in the flight rats on landing day and 30 days after landing. Some of these changes appear to be permanent. Several conclusions can be drawn from these studies: (1) Many aspects of motor behavior are preprogrammed into the young nervous system. In addition, several aspects of motor behavior are acquired as a function of the interaction of the developing organism and the rearing environment; (2) Widespread neuroanatomical differences between one-G- and microgravity-reared rats indicate that there is a structural basis for the adaptation to the rearing environment. These observations provide support for the idea that an animal's motor system adapts for optimal function within the environment experienced during a critical period in early postnatal life.