The temporal and spatial distributions of several growth factors suggest roles in the regulation of neuronal differentiation in the neocortex. Among such growth factors, the insulin-like growth factors (IGF-I and -II) are of particular interest because they are available to neurons from multiple sources under independent control. IGF-I is produced by many neurons throughout the brain and also by cells in the cerebral vasculature. IGF-II is found at high levels in the CSF, and both IGF-I and IGF-II cross the blood-brain barrier. Thus, the IGFs may act as both paracrine and endocrine regulators of neuronal development. As an initial step toward understanding the influence of IGFs in the developing cerebral cortex, the present study examined the effects of IGF-I and of the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) on the dendritic complexity of layer 2 pyramidal neurons. The results demonstrate that IGF-I increased the branching and total extent of both apical and basal dendrites of pyramidal cells in organotypic slices of rat primary somatosensory cortex. BDNF and NT-3 also enhanced dendritic development, but the two neurotrophins increased the extent of only basal, not apical, dendrites and promoted greater elongation than was seen after IGF-I treatment. These results provide direct evidence that IGF-I can regulate the dendritic elaboration of cortical neurons and indicate that endogenous IGFs may influence dendritic differentiation and the formation of cortical connections. In addition, IGF-dependent regulation of dendritic structure may represent a link between age-related declines in IGFs and cognitive deficits seen in senescence.

Serotonergic receptor binding is altered in the medullary serotonergic nuclei, including the paragigantocellularis lateralis (PGCL), in many infants who die of sudden infant death syndrome (SIDS). The PGCL receives inputs from many sites in the caudal brainstem and projects to the spinal cord and to more rostral areas important for arousal and vigilance. We have shown previously that local unilateral nonspecific neuronal inhibition in this region with GABA A agonists disrupts sleep architecture. We hypothesized that specifically inhibiting serotonergic activity in the PGCL would result in less sleep and heightened vigilance. We analyzed sleep before and after unilaterally dialyzing the 5-HT 1A agonist (

Acute inhibition of serotonergic (5-HT) neurons in the medullary raphé (MR) using a 5-HT(1A) receptor agonist had an age-dependent impact on the "CO(2) response" of piglets (33). Our present study explored the effect of chronic 5-HT neuron lesions in the MR and extra-raphé on the ventilatory response to hypercapnia and hypoxia in piglets, with possible implications on the role of 5-HT in the sudden infant death syndrome. We established four experimental groups. Group 1 (n = 11) did not undergo any treatment. Groups 2, 3, and 4 were injected with either vehicle or the neurotoxin 5,7-dihydroxytryptamine in the cisterna magna during the first week of life (group 2, n = 9; group 4, n = 11) or second week of life (group 3, n = 10). Ventilation was recorded in response to 5% CO(2) (all groups) and 12% O(2) (group 2) during wakefulness and sleep up to postnatal day 25. Surprisingly, the piglets did not reveal changes in their CO(2) sensitivity during early postnatal development. Overall, considerable lesions of 5-HT neurons (up to 65% decrease) in the MR and extra-raphé had no impact on the CO(2) response, regardless of injection time. Postlesion raphé plasticity could explain why we observed no effect. 5,7-Dihydroxytryptamine-treated males, however, did present a lower CO(2) response during sleep. Hypoxia significantly altered the frequency during sleep in lesioned piglets. Further studies are necessary to elucidate the role of plasticity, sex, and 5-HT abnormalities in sudden infant death syndrome.

The laryngeal chemoreflex (LCR) is elicited by water in the larynx and leads to apnea and respiratory disruption in immature animals. The LCR is exaggerated by the elevation of brain temperature within or near the nucleus of the solitary tract (NTS) in decerebrate piglets. Thermal prolongation of reflex apnea elicited by superior laryngeal nerve stimulation is reduced by systemic administration of GABA(A) receptor antagonists. Therefore, we tested the hypothesis that microdialysis within or near the NTS of gabazine, a GABA(A) receptor antagonist, would reverse thermal prolongation of the LCR. We examined this hypothesis in 21 decerebrate piglets (age 3-13 days). We elicited the LCR by injecting 0.1 ml of water into the larynx before and after each piglet's body temperature was elevated by approximately 2.5 degrees C and before and after 2-5 mM gabazine was dialyzed unilaterally and focally in the medulla. Elevated body temperature failed to prolong the LCR in one piglet, which was excluded from analysis. Elevated body temperature prolonged the LCR in all the remaining animals, and dialysis of gabazine into the region near the NTS (n = 10) reversed the thermal prolongation of the LCR even though body temperature remained elevated. Dialysis of gabazine in other medullary sites (n = 10) did not reverse thermal prolongation of the LCR. Gabazine had no consistent effect on baseline respiratory activity during hyperthermia. These findings are consistent with the hypothesis that hyperthermia activates GABAergic mechanisms in or near the NTS that are necessary for the thermal prolongation of the LCR.

Sensory perception can be severely degraded after peripheral injuries that disrupt the functional organization of the sensory maps in somatosensory cortex, even after nerve regeneration has occurred. Rehabilitation involving sensory retraining can improve perceptual function, presumably through plasticity mechanisms in the somatosensory processing network. However, virtually nothing is known about the effects of rehabilitation strategies on brain organization, or where the effects are mediated. In this study, five macaque monkeys received months of enriched sensory experience after median nerve cut and repair early in life. Subsequently, the sensory representation of the hand in primary somatosensory cortex was mapped using multiunit microelectrodes. Additionally, the primary somatosensory relay in the thalamus, the ventroposterior nucleus, was studied to determine whether the effects of the enrichment were initiated subcortically or cortically. Age-matched controls included six monkeys with no sensory manipulation after median nerve cut and regeneration, and one monkey that had restricted sensory experience after the injury. The most substantial effect of the sensory environment was on receptive field sizes in cortical area 3b. Significantly greater proportions of cortical receptive fields in the enriched monkeys were small and well localized compared to the controls, which showed higher proportions of abnormally large or disorganized fields. The refinements in receptive field size and extent in somatosensory cortex likely provide better resolution in the sensory map and may explain the improved functional outcomes after rehabilitation in humans.