Rick C.S. Lin

Neonatal Antidepressant Exposure has Lasting Effects on Behavior and Serotonin Circuitry

A significant fraction of infants born to mothers taking selective serotonin reuptake inhibitors (SSRIs) during late pregnancy display clear signs of antidepressant withdrawal indicating that these drugs can penetrate fetal brain in utero at biologically significant levels. Previous studies in rodents have demonstrated that early exposure to some antidepressants can result in persistent abnormalities in adult behavior and indices of monoaminergic activity. Here, we show that chronic neonatal (postnatal days 8–21) exposure to citalopram (5 mg/kg, twice daily, s.c.), a potent and highly selective SSRI, results in profound reductions in both the rate-limiting serotonin synthetic enzyme (tryptophan hydroxylase) in dorsal raphe and in serotonin transporter expression in cortex that persist into adulthood. Furthermore, neonatal exposure to citalopram produces selective changes in behavior in adult rats including increased locomotor activity and decreased sexual behavior similar to that previously reported for antidepressants that are nonselective monoamine transport inhibitors. These data indicate that the previously reported neurobehavioral effects of antidepressants are a consequence of their effects on the serotonin transporter. Moreover, these data argue that exposure to SSRIs at an early age can disrupt the normal maturation of the serotonin system and alter serotonin-dependent neuronal processes. It is not known whether this effect of SSRIs is paralleled in humans; however, these data suggest that in utero, exposure to SSRIs may have unforeseen long-term neurobehavioral consequences.

Re-expression of the intermediate filament nestin in reactive astrocytes ☆

The intermediate filament nestin is highly expressed in multipotential stem cells of the developing central nervous system (CNS). During neuro- and gliogenesis, nestin is replaced by cell type-specific intermediate filaments, e.g. neurofilaments and glial fibrillary acidic protein (GFAP). In this study, we demonstrate that nestin expression is re-induced in reactive astrocytes in the lesioned adult brain. Following ischaemic and mechanical lesioning, a strong and sustained expression of nestin was noted in GFAP-positive cells surrounding the lesion site. Lesion experiments in transgenic mice carrying the lacZ gene under control of regulatory sequences from the nestin gene suggested that the upregulation of nestin in reactive astrocytes is mediated via the same sequences that control nestin expression during CNS development. These observations and recent data on the co-expression of glial and neuronal marker antigens in reactive astrocytes point to a close relationship between proliferating astrocytes and neuroepithelial precursor cells.

Microtubule‐Associated Protein 2 as an Early Indicator of Ischemia‐Induced Neurodegeneration in the Gerbil Forebrain

Abstract: Microtubule‐associated protein 2 (MAP‐2) was studied in the gerbil hippocampus and striatum after transient ischemia. Western immunoblot analysis shows that there is a significant decrease of MAP‐2 in the dorsolateral sector of the striatum and a slight decrease of MAP‐2 in the CA1 region of the hippocampus 6–12 h after ischemia in the gerbil forebrain. The immunohistochemical staining pattern of MAP‐2 in these two regions also shows a loss of immunostaining of MAP‐2. In particular, a beaded MAP‐2 immunostaining pattern at the apical dendritic region of the CA1 neurons of the hippocampus was found within 12 h after ischemia compared with the smooth dendritic immunostaining of MAP‐2 in normal CA1 neurons. In vitro assays of MAP‐2 degradation suggest that dendritic loss of immunoreactivity after ischemia seen on western blots may be due to calpain I degradation of MAP‐2. Loss of MAP‐2 in both the striatum and hippocampus was found to occur earlier than spectrin degradation by western blot analysis. These results suggest that loss of MAP‐2 may participate in the initial phase of neuronal dysfunction and that dendritic breakdown may be a first sign of neurodegeneration.

Somatotopic maps within the zona incerta relay parallel GABAergic somatosensory pathways to the neocortex, superior colliculus, and brainstem

Neurons located in the zona incerta (ZI) of the ventral thalamus project to several regions of the central nervous system, including the neocortex, superior colliculus, and brainstem. However, whether these projections are functionally segregated remains unknown. This issue was addressed here by combining neuroanatomical tracers with immunohistochemical staining for gamma-aminobutyric acid (GABA) and/or parvalbumin, coupled with neurophysiological mapping. GABAergic projection neurons were found in four distinct subregions of the ZI including: (1) the rostral pole of the ZI, from which neurons project to the supragranular layers of the neocortex (especially layer I); (2) the dorsal subregion of the ZI, where both ascending projections to the neocortex and descending projections to the pretectal area were observed; (3) the ventral subregion of the ZI, whose neurons project to the superior colliculus; and 3) the caudal pole of the ZI, from which descending projections to the lower brainstem and spinal cord were observed. Somatotopic representations of the contralateral cutaneous periphery were also identified in the dorsal and ventral subregions of ZI, both of which were found to receive dense direct afferent projections from the trigeminal complex, and dorsal column nuclei. These results suggest that the rat ZI is a major somatosensory relay in the ventral thalamus, carrying feed-forward inhibitory signals to neocortical and subcortical targets, in parallel with the excitatory somatosensory pathways.

Lateralization and functional organization of the locus coeruleus projection to the trigeminal somatosensory pathway in rat

The primary goals of this study were to (1) examine the distribution of locus coeruleus (LC) neurons, which project to cortical and subcortical sites along the trigeminal somatosensory pathway in rats, and (2) determine the extent to which different regions within this ascending sensory system receive collateral projections from the same LC neuron. Long‐Evans hooded rats received unilateral pressure injections of different combinations of retrograde fluorescent tracers into whisker‐related regions of primary (SI) and secondary (SII) somatosensory cortices, the ventrobasal (VB) and posterior group (POm) nuclei of the thalamus, and the principalis nucleus of the trigeminal complex (PrV). Coronal sections (40–100 μm) through the LC were examined by fluorescence microscopy, and the distribution of retrogradely labeled cells was recorded. The major finding was that whisker‐related regions of the cortex receive efferent projections from neurons concentrated in the caudal portion of the ipsilateral LC, whereas subcortical trigeminal somatosensory structures receive bilateral input from both LC nuclei. Despite the bilateral nature of the LC projection to subcortical sites, the majority of LC efferents to VB and POm thalamus originate in the ipsilateral LC nucleus, whereas projections to PrV originate primarily from the contralateral LC. An additional finding was that a relatively large proportion of LC cells, which project to a single somatosensory structure, also send axon collaterals to other relay sites along the same ascending somatosensory pathway. Taken together, these results suggest that the LC–noradrenergic system maintains a more selective relationship with functionally related efferent targets than has been previously appreciated. J. Comp. Neurol. 385:135–147, 1997.

Perinatal antidepressant exposure alters cortical network function in rodents

Serotonin (5-HT) plays a key role in early brain development, and manipulation of 5-HT levels during this period can have lasting neurobiological and behavioral consequences. It is unclear how perinatal exposure to drugs, such as selective serotonin reuptake inhibitors (SSRIs), impacts cortical neural network function and what mechanism(s) may elicit the disruption of normal neuronal connections/interactions. In this article, we report on cortical wiring organization after pre- and postnatal exposure to the SSRI citalopram. We show that manipulation of 5-HT during early development in both in vitro and in vivo models disturbs characteristic chemoarchitectural and electrophysiological brain features, including changes in raphe and callosal connections, sensory processing, and myelin sheath formation. Also, drug-exposed rat pups exhibit neophobia and disrupted juvenile play behavior. These findings indicate that 5-HT homeostasis is required for proper brain maturation and that fetal/infant exposure to SSRIs should be examined in humans, particularly those with developmental dysfunction, such as autism.

Recovery of functional and structural age-related changes in the rat primary auditory cortex with operant training

Cognitive decline is a virtually universal aspect of the aging process. However, its neurophysiological basis remains poorly understood. We describe here more than 20 age-related cortical processing deficits in the primary auditory cortex of aging versus young rats that appear to be strongly contributed to by altered cortical inhibition. Consistent with these changes, we recorded in old rats a decrease in parvalbumin-labeled inhibitory cortical neurons. Furthermore, old rats were slower to master a simple behavior, with learning progressions marked by more false-positive responses. We then examined the effect of intensive auditory training on the primary auditory cortex in these aged rats by using an oddball discrimination task. Following training, we found a nearly complete reversal of the majority of previously observed functional and structural cortical impairments. These findings suggest that age-related cognitive decline is a tightly regulated plastic process, and demonstrate that most of these age-related changes are, by their fundamental nature, reversible.

Topographic organization and neurochemical identity of dorsal raphe neurons that project to the trigeminal somatosensory pathway in the rat

The primary goals of this study were to: 1) examine the distribution of neurons within the dorsal raphe (DR) nucleus that project to cortical and subcortical sites along the trigeminal somatosensory pathway in rat; 2) determine the extent to which different regions within this ascending sensory system receive collateral projections from the same DR neuron; and 3) identify the putative transmitters contained within these DR projection neurons. Long‐Evans hooded rats received pressure injections of various combinations of retrograde fluorescent tracers; into the whisker‐related regions of the primary somatosensory cortex (barrel field cortex [BC]), ventral posterior medial thalamus (VPM), and principal nucleus of the trigeminal complex (PrV). The distribution of retrogradely labeled neurons within the DR was examined by fluorescence microscopy. The major finding was that cortically projecting neurons were located within the midline regions of the rostral portion of the DR, whereas cells projecting to subcortical trigeminal somatosensory structures were distributed bilaterally in the lateral wing regions of the DR as well as in the midline portions of the nucleus. Single neurons that send axon collaterals to multiple cortical and subcortical trigeminal somatosensory targets were observed in the dorsomedian and ventromedian regions of the DR. DR neurons that projected to cortical and subcortical sites contained serotonin but not tyrosine hydroxylase, the marker enzyme for catecholamine transmitters. Taken together, these findings provide further evidence of neurochemical specificity and functional anatomical organization within the DR efferent projection system. J. Comp. Neurol. 435:325–340, 2001.

Chronic administration of selective adenosine A1 receptor agonist or antagonist in cerebral ischemia

The effect of chronic administration of selective adenosine A1 receptor agonists and antagonists on the outcome of cerebral ischemia is entirely unknown. Therefore, we have investigated the impact of such regimens on the hippocampal adenosine A1 receptor density, and on the recovery from 10 min forebrain ischemia in gerbils. While acutely administered N6-cyclopentyladenosine (CPA) given at 0.02 mg/kg resulted only in a significant reduction of mortality, at 1 mg/kg it improved both survival and neuronal preservation in the hippocampal CA1 region. Acute treatment with 1,3-dipropyl-8-cyclopentylxanthine (CPX) significantly worsened the outcome and enhanced neuronal destruction. The effects of chronic administration of these drugs (15 days followed by 1 drug-free day) were opposite. Thus, although chronic CPA at 0.02 mg/kg did not have any effect at all, at 1 mg/kg both survival and neuronal preservation were significantly poorer than in controls, while chronic CPX resulted in a significant improvement of both measures. These results were not accompanied by adenosine A1 receptor up- or downregulation. Our study indicates that highly selective adenosine analogues may have therapeutic potential in treatment of cerebral ischemia/stroke and possibly other neurodegenerative disorders as well.

Internucleosomal DNA fragmentation in gerbil hippocampus following forebrain ischemia.

Internucleosomal DNA fragmentation, the characteristics feature of programmed cell death, was demonstrated in gerbil hippocampus following 10 min of forebrain ischemia. Quantitative analysis revealed the presence of DNA fragments as early as 12 h after ischemia, reaching a maximum at 48 h. Measurable DNA fragmentation was still present in 3/3 subjects 96 h after the ischemic insult. In situ staining of hippocampus demonstrated pronounced DNA fragmentation that was localized in the CA1 region. The localization of fragmented DNA to the CA1 is consistent with the vulnerability of this layer to ischemic insult, and indicates that DNA fragmentation may be associated with the delayed loss of CA1 neurons in this model of forebrain ischemia.