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1.  Age-related loss of orexin/hypocretin neurons 
Neuroscience  2011;178:82-88.
Aging is associated with many physiological alterations—such as changes in sleep patterns, metabolism and food intake—suggestive of hypothalamic dysfunction, but the effects of senescence on specific hypothalamic nuclei and neuronal groups that mediate these alterations is unclear. The lateral hypothalamus and contiguous perifornical area (LH/PFA) contains several populations of neurons, including those that express the neuropeptides orexin (hypocretin) or melanin-concentrating hormone (MCH). Collectively, orexin and MCH neurons influence many integrative homeostatic processes related to wakefulness and energy balance. Here, we determined the effect of aging on numbers of orexin and MCH neurons in young adult (3–4 months) and old (26–28 months) Fisher 344/Brown Norway F1 hybrid rats. Aged rats exhibited a loss of greater than 40% of orexin-immunoreactive neurons in both the medial and lateral (relative to the fornix) sectors of the LH/PFA. MCH-immunoreactive neurons were also lost in aged rats, primarily in the medial LH/PFA. Neuronal loss in this area was not global as no change in cells immunoreactive for the pan-neuronal marker, NeuN, was observed in aged rats. Combined with other reports of altered receptor expression or behavioral responses to exogenously-administered neuropeptide, these data suggest that compromised orexin (and, perhaps, MCH) function is an important mediator of age-related homeostatic disturbances of hypothalamic origin. The orexin system may represent a crucial substrate linking homeostatic and cognitive dysfunction in aging, as well as a novel therapeutic target for pharmacological or genetic restoration approaches to preventing or ameliorating these disturbances.
doi:10.1016/j.neuroscience.2011.01.031
PMCID: PMC3048917  PMID: 21262323
orexin; hypocretin; melanin concentrating hormone; hypothalamus; aging; energy balance
2.  Concurrent upregulation of postsynaptic L-type Ca2+ channel function and protein kinase A signaling is required for the periadolescent facilitation of Ca2+ plateau potentials and dopamine D1 receptor modulation in the prefrontal cortex 
Neuropharmacology  2011;60(6):953-962.
Further understanding of how prefrontal cortex (PFC) circuit change during postnatal development is of great interest due to its role in working memory and decision-making, two cognitive abilities that are refined late in adolescence and become altered in schizophrenia. While it is evident that dopamine facilitation of glutamate responses occurs during adolescence in the PFC, little is known about the cellular mechanisms that support these changes. Among them, a developmental facilitation of postsynaptic Ca2+ function is of particular interest given its role in coordinating neuronal ensembles, a process thought to contribute to maturation of PFC function. Here we conducted whole-cell patch clamp recordings of deep-layer pyramidal neurons in PFC brain slices and determined how somatic-evoked Ca2+-mediated plateau depolarizations change throughout postnatal day (PD) 25 (juvenile) to adulthood (PD 80). Postsynaptic Ca2+ potentials in the PFC increase in duration throughout postnatal development. A remarkable shift from short to prolonged depolarizations was observed after PD 40. This change is reflected by an enhancement of L-type Ca2+ channel function and postsynaptic PKA signaling. We speculate that such a protracted developmental facilitation of Ca2+ response in the PFC may contribute to improvement of working memory performance through adolescence.
doi:10.1016/j.neuropharm.2011.01.041
PMCID: PMC3077898  PMID: 21288471
adolescence; postsynaptic plasticity; electrophysiology; plateau potentials
3.  Effects of ethanol during adolescence on the number of neurons and glia in the medial prefrontal cortex and basolateral amygdala of adult male and female rats 
Brain Research  2012;1466:24-32.
Human adolescents often consume alcohol in a binge-like manner at a time when changes are occurring within specific brain structures, such as the medial prefrontal cortex (mPFC) and the basolateral nucleus of the amygdala (BLN). In particular, neuron and glia number are changing in both of these areas in the rat between adolescence and adulthood (Markham et al., 2007; Rubinow and Juraska, 2009). The current study investigated the effects of ethanol exposure during adolescence on the number of neurons and glia in the adult mPFC and BLN in Long-Evans male and female rats. Saline or 3 g/kg ethanol was administered between postnatal days (P) 35–45 in a binge-like pattern, with 2 days of injections followed by 1 day without an injection. Stereological analyses of the ventral mPFC (prelimbic and infralimbic areas) and the BLN were performed on brains from rats at 100 days of age. Neuron and glia densities were assessed with the optical disector and then multiplied by the volume to calculate the total number of neurons and glia. In the adult mPFC, ethanol administration during adolescence resulted in a decreased number of glia in males, but not females, and had no effect on the number of neurons. Adolescent ethanol exposure had no effects on glia or neuron number in the BLN. These results suggest that glia cells in the prefrontal cortex are particularly sensitive to binge-like exposure to ethanol during adolescence in male rats only, potentially due to a decrease in proliferation in males or protective mechanisms in females.
doi:10.1016/j.brainres.2012.05.023
PMCID: PMC3389213  PMID: 22627163
alcohol; sex differences; stereology; cell death; cell proliferation
4.  Longitudinal Brain Changes in Early-Onset Psychosis 
Schizophrenia Bulletin  2008;34(2):341-353.
Progressive losses of cortical gray matter volumes and increases in ventricular volumes have been reported in patients with childhood-onset schizophrenia (COS) during adolescence. Longitudinal studies suggest that the rate of cortical loss seen in COS during adolescence plateaus during early adulthood. Patients with first-episode adolescent-onset schizophrenia show less marked progressive changes, although the number of studies in this population is small. Some studies show that, although less exaggerated, progressive changes are also present in nonschizophrenia early-onset psychosis. The greater loss of brain tissue seen in COS, even some years after the first episode, as compared to adolescent- or adult-onset schizophrenia may be due to variables such as sample bias (more severe, treatment refractory sample of childhood-onset patients studied), a process uniquely related to adolescent development in COS, differential brain effects of drug treatment in this population, clinical outcome, or interactions among these variables. Findings from both cross-sectional studies of first-episode patients and longitudinal studies in COS and adolescent onset support the concept of early-onset schizophrenia as a progressive neurodevelopmental disorder with both early and late developmental abnormalities. Future studies should look for correlates at a cellular level and for pathophysiological explanations of volume changes in these populations. The association of risk genes involved in circuitries associated with schizophrenia and their relationship to developmental trajectories is another promising area of future research.
doi:10.1093/schbul/sbm157
PMCID: PMC2632400  PMID: 18234701
early-onset; MRI; children; adolescents; psychosis; neurodevelopment
5.  Disruption of Neuronal Autophagy by Infected Microglia Results in Neurodegeneration 
PLoS ONE  2008;3(8):e2906.
There is compelling evidence to support the idea that autophagy has a protective function in neurons and its disruption results in neurodegenerative disorders. Neuronal damage is well-documented in the brains of HIV-infected individuals, and evidence of inflammation, oxidative stress, damage to synaptic and dendritic structures, and neuronal loss are present in the brains of those with HIV-associated dementia. We investigated the role of autophagy in microglia-induced neurotoxicity in primary rodent neurons, primate and human models. We demonstrate here that products of simian immunodeficiency virus (SIV)-infected microglia inhibit neuronal autophagy, resulting in decreased neuronal survival. Quantitative analysis of autophagy vacuole numbers in rat primary neurons revealed a striking loss from the processes. Assessment of multiple biochemical markers of autophagic activity confirmed the inhibition of autophagy in neurons. Importantly, autophagy could be induced in neurons through rapamycin treatment, and such treatment conferred significant protection to neurons. Two major mediators of HIV-induced neurotoxicity, tumor necrosis factor-α and glutamate, had similar effects on reducing autophagy in neurons. The mRNA level of p62 was increased in the brain in SIV encephalitis and as well as in brains from individuals with HIV dementia, and abnormal neuronal p62 dot structures immunoreactivity was present and had a similar pattern with abnormal ubiquitinylated proteins. Taken together, these results identify that induction of deficits in autophagy is a significant mechanism for neurodegenerative processes that arise from glial, as opposed to neuronal, sources, and that the maintenance of autophagy may have a pivotal role in neuroprotection in the setting of HIV infection.
doi:10.1371/journal.pone.0002906
PMCID: PMC2483417  PMID: 18682838
6.  Aging Reduces Total Neuron Number in the Dorsal Component of the Rodent Prefrontal Cortex 
The Journal of comparative neurology  2012;520(6):1318-1326.
For many years, aging was thought to be accompanied by significant decreases in total neuron number across multiple brain regions. However, this view was revised with the advent of modern quantification methods, and it is now widely accepted that the hippocampus and many regions of the cortex show substantially preserved numbers of neurons during normal aging. Nonetheless, age-related changes in neuron number do occur in focal regions of the primate prefrontal cortex (PFC), but the question of whether age-related neuron loss is an exclusive characteristic of the PFC in primates remains relatively unexplored. To investigate the loss of neurons with normal aging in rodents, we used unbiased stereological methods to quantify the number of principal neurons and interneurons in the PFC of young and aged rats. We observed a significant age-related decline in the number of principal neurons in the dorsal PFC. The number of interneurons positively stained with antibodies to glutamic acid decarboxylase 67 was also reduced in the dorsal PFC of aged rats. These observations indicate that the dorsal PFC is susceptible to neuron loss with aging in rodent brain and suggest some common basis for vulnerability in cortical circuits across species.
doi:10.1002/cne.22790
PMCID: PMC3931233  PMID: 22020730
cingulate cortex; stereology; GAD67; interneuron
7.  Low Dose Prenatal Ethanol Exposure Induces Anxiety-Like Behaviour and Alters Dendritic Morphology in the Basolateral Amygdala of Rat Offspring 
PLoS ONE  2013;8(1):e54924.
Prenatal exposure to high levels of alcohol is strongly associated with poor cognitive outcomes particularly in relation to learning and memory. It is also becoming more evident that anxiety disorders and anxiety-like behaviour can be associated with prenatal alcohol exposure. This study used a rat model to determine if prenatal exposure to a relatively small amount of alcohol would result in anxiety-like behaviour and to determine if this was associated with morphological changes in the basolateral amygdala. Pregnant Sprague Dawley rats were fed a liquid diet containing either no alcohol (Control) or 6% (vol/vol) ethanol (EtOH) throughout gestation. Male and Female offspring underwent behavioural testing at 8 months (Adult) or 15 months (Aged) of age. Rats were perfusion fixed and brains were collected at the end of behavioural testing for morphological analysis of pyramidal neuron number and dendritic morphology within the basolateral amygdala. EtOH exposed offspring displayed anxiety-like behaviour in the elevated plus maze, holeboard and emergence tests. Although sexually dimorphic behaviour was apparent, sex did not impact anxiety-like behaviour induced by prenatal alcohol exposure. This increase in anxiety – like behaviour could not be attributed to a change in pyramidal cell number within the BLA but rather was associated with an increase in dendritic spines along the apical dendrite which is indicative of an increase in synaptic connectivity and activity within these neurons. This study is the first to link increases in anxiety like behaviour to structural changes within the basolateral amygdala in a model of prenatal ethanol exposure. In addition, this study has shown that exposure to even a relatively small amount of alcohol during development leads to long term alterations in anxiety-like behaviour.
doi:10.1371/journal.pone.0054924
PMCID: PMC3559882  PMID: 23383000
8.  PRENATAL EXPOSURE TO ETHANOL AFFECTS POSTNATAL NEUROGENESIS IN THALAMUS 
Experimental neurology  2010;223(2):566-573.
The number of neurons in the ventrobasal thalamus (VB) in the adolescent rat is unaffected by prenatal exposure to ethanol. This is in sharp contrast to other parts of the trigeminal-somatosensory system which exhibit 30–35% fewer neurons after prenatal ethanol exposure. The present study tested the hypothesis that prenatal ethanol exposure affects dynamic changes in the numbers of VB neurons; such changes reflect the sum of cell proliferation and death. Neuronal number in the VB was determined during the first postnatal month in the offspring of pregnant Long-Evans rats fed an ethanol-containing diet or pair-fed an isocaloric non-alcoholic liquid diet. Offspring were examined between postnatal day (P) 1 and P30. The size of the VB and neuronal number were determined stereologically. Prenatal exposure to ethanol did not significantly alter neuronal number on any individual day, nor was the prenatal generation of VB neurons affected. Interestingly, prenatal ethanol exposure did affect the pattern of the change in neuronal number over time; total neuronal number was stable in the ethanol-treated pups after P12, but it continued to rise in the controls until P21. In addition, the rate of cell proliferation during the postnatal period was greater in ethanol-treated animals. Thus, the rate of neuronal acquisition is altered by ethanol, and by deduction there appears to be less ethanol-induced neuronal loss in the VB. A contributor to these changes is a latent effect of ethanol on postnatal neurogenesis in the VB and the apparent survival of new neurons.
doi:10.1016/j.expneurol.2010.02.003
PMCID: PMC2864341  PMID: 20170653
alcohol; brain development; fetal alcohol spectrum disorder; fetal alcohol syndrome; neural stem cell; proliferation; somatosensory; trigeminal; ventrobasal
9.  Regional variability in age-related loss of neurons from the primary visual cortex and medial prefrontal cortex of male and female rats 
Brain research  2008;1218:1-12.
During aging, changes in the structure of the cerebral cortex of the rat have been seen, but potential changes in neuron number remain largely unexplored. In the present study, stereological methods were used to examine neuron number in the medial prefrontal cortex and primary visual cortex of young adult (85–90 days of age) and aged (19–22 months old) male and female rats in order to investigate any age-related losses. Possible sex differences in aging were also examined since sexually dimorphic patterns of aging have been seen in other measures. An age-related loss of neurons (18–20%), which was mirrored in volume losses, was found to occur in the primary visual cortex in both sexes in all layers except IV. Males, but not females, also lost neurons (15 %) from layer V/VI of the ventral medial prefrontal cortex and showed an overall decrease in volume of this region. In contrast, dorsal medial prefrontal cortex showed no age-related changes. The effects of aging clearly differ among regions of the rat brain and to some degree, between the sexes.
doi:10.1016/j.brainres.2008.04.055
PMCID: PMC2538957  PMID: 18513705
Nervous system development; regeneration; aging; sex differences; stereology; neuron number; volume; aging; anterior cingulate
10.  Postnatal brain development: Structural imaging of dynamic neurodevelopmental processes 
Progress in brain research  2011;189:77-92.
After birth, there is striking biological and functional development of the brain’s fiber tracts as well as remodeling of cortical and subcortical structures. Behavioral development in children involves a complex and dynamic set of genetically guided processes by which neural structures interact constantly with the environment. This is a protracted process, beginning in the third week of gestation and continuing into early adulthood. Reviewed here are studies using structural imaging techniques, with a special focus on diffusion weighted imaging, describing age-related brain maturational changes in children and adolescents, as well as studies that link these changes to behavioral differences. Finally, we discuss evidence for effects on the brain of several factors that may play a role in mediating these brain–behavior associations in children, including genetic variation, behavioral interventions, and hormonal variation associated with puberty. At present longitudinal studies are few, and we do not yet know how variability in individual trajectories of biological development in specific neural systems map onto similar variability in behavioral trajectories.
doi:10.1016/B978-0-444-53884-0.00019-1
PMCID: PMC3690327  PMID: 21489384
MRI; DTI; brain development; cognitive development; individual differences; fiber tracts
11.  Developmental trajectories during adolescence in males and females: a cross-species understanding of underlying brain changes 
Adolescence is a transitional period between childhood and adulthood that encompasses vast changes within brain systems that parallel some, but not all, behavioral changes. Elevations in emotional reactivity and reward processing follow an inverted U shape in terms of onset and remission, with the peak occurring during adolescence. However, cognitive processing follows a more linear course of development. This review will focus on changes within key structures and will highlight the relationships between brain changes and behavior, with evidence spanning from functional magnetic resonance imaging (fMRI) in humans to molecular studies of receptor and signaling factors in animals. Adolescent changes in neuronal substrates will be used to understand how typical and atypical behaviors arise during adolescence. We draw upon clinical and preclinical studies to provide a neural framework for defining adolescence and its role in the transition to adulthood.
doi:10.1016/j.neubiorev.2011.04.013
PMCID: PMC3134153  PMID: 21600919
Adolescence; gray matter; pruning; sex differences; white matter
12.  Clathrin assembly proteins AP180 and CALM in the embryonic rat brain 
The Journal of comparative neurology  2010;518(18):3803-3818.
Clathrin-coated vesicles are known to play diverse and pivotal roles in cells. The proper formation of clathrin-coated vesicles is dependent on, and highly regulated by, a large number of clathrin assembly proteins. These assembly proteins likely determine the functional specificity of clathrin-coated vesicles, and together they control a multitude of intracellular trafficking pathways—including those involved in embryonic development. In this study, we focus on two closely related clathrin assembly proteins, AP180 and CALM (clathrin assembly lymphoid myeloid leukemia protein), in the developing embryonic rat brain. We find that AP180 begins to be expressed at embryonic day 14 (E14), but only in postmitotic cells that have acquired a neuronal fate. CALM, on the other hand, is expressed as early as E12, by both neural stem cells and postmitotic neurons. In vitro loss-of-function studies using RNA interference (RNAi) indicate that AP180 and CALM are dispensable for some aspects of embryonic neurogenesis but are required for the growth of postmitotic neurons. These results identify the developmental staging of AP180 and CALM expression and suggest that each protein has distinct functions in neural development.
doi:10.1002/cne.22425
PMCID: PMC2909614  PMID: 20653035
intracellular trafficking; neural stem cells; postmitotic neurons; dopaminergic
13.  BDNF is required for the survival of differentiated geniculate ganglion neurons 
Developmental biology  2010;340(2):419-429.
In mice lacking functional brain-derived neurotrophic factor (BDNF), the number of geniculate ganglion neurons, which innervate taste buds, is reduced by one-half. Here, we determined how and when BDNF regulates the number of neurons in the developing geniculate ganglion. The loss of geniculate neurons begins at embryonic day 13.5 (E13.5) and continues until E18.5 in BDNF-null mice. Neuronal loss in BDNF-null mice was prevented by removal of the pro-apoptotic gene Bax. Thus, BDNF regulates embryonic geniculate neuronal number by preventing cell death rather than promoting cell proliferation. The number of neurofilament-positive neurons expressing activated caspase-3 increased on E13.5 in bdnf −/− mice, compared to wild-type mice, demonstrating that differentiated neurons were dying. The axons of geniculate neurons approach their target cells, the fungiform papillae, beginning on E13.5, at which time we found robust BDNFLacZ expression in these targets. Altogether, our findings establish that BDNF produced in peripheral target cells regulates the survival of early geniculate neurons by inhibiting cell death of differentiated neurons on E13.5 of development. Thus, BDNF acts as a classic target-derived growth factor in the developing taste system.
doi:10.1016/j.ydbio.2010.01.024
PMCID: PMC2854215  PMID: 20122917
BDNF; gustatory/geniculate neurons; taste development; Bax; BDNFLacZ; activated caspase-3
14.  dcc orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients 
Translational Psychiatry  2013;3(12):e338-.
Adolescence is a period of heightened susceptibility to psychiatric disorders of medial prefrontal cortex (mPFC) dysfunction and cognitive impairment. mPFC dopamine (DA) projections reach maturity only in early adulthood, when their control over cognition becomes fully functional. The mechanisms governing this protracted and unique development are unknown. Here we identify dcc as the first DA neuron gene to regulate mPFC connectivity during adolescence and dissect the mechanisms involved. Reduction or loss of dcc from DA neurons by Cre-lox recombination increased mPFC DA innervation. Underlying this was the presence of ectopic DA fibers that normally innervate non-cortical targets. Altered DA input changed the anatomy and electrophysiology of mPFC circuits, leading to enhanced cognitive flexibility. All phenotypes only emerged in adulthood. Using viral Cre, we demonstrated that dcc organizes mPFC wiring specifically during adolescence. Variations in DCC may determine differential predisposition to mPFC disorders in humans. Indeed, DCC expression is elevated in brains of antidepressant-free subjects who committed suicide.
doi:10.1038/tp.2013.105
PMCID: PMC4030324  PMID: 24346136
dopamine; neurodevelopmental disorders; neural circuit formation; prefrontal cortex dysfunction; resilience
15.  The Effects of Aging on Hypoglossal Motoneurons in Rats 
Dysphagia  2008;24(1):40-48.
Aging can result in a loss of neuronal cell bodies and a decrease in neuronal size in some regions of the brain and spinal cord. Motoneuron loss in the spinal cord is thought to contribute to the progressive decline in muscle mass and strength that occurs with age (sarcopenia). Swallowing disorders represent a large clinical problem in elderly persons; however, age-related alterations in cranial motoneurons that innervate muscles involved in swallowing have been understudied. We aimed to determine if age-related alterations occurred in the hypoglossal nucleus in the brainstem. If present, these changes might help explain alterations at the neuromuscular junction and changes in the contractile properties of tongue muscle that have been reported in older rats. We hypothesized that with increasing age, there would be a loss of motoneurons and a reduction in neuronal size and the number of primary dendrites associated with each hypoglossal motoneuron. Neurons in the hypoglossal nucleus were visualized with the neuronal marker NeuN in young (9–10 months), middle-aged (24–25 months), and old (32–33 months) male F344/BN rats. Hypoglossal motoneurons were retrograde labeled with injections of Cholera Toxin β into the genioglossus muscle of the tongue and visualized using immunocytochemistry. Results indicated that the number of primary dendrites of hypoglossal motoneurons decreased significantly with age, while no age-associated changes were found in the number or size of hypoglossal motoneurons. Loss of primary dendrites could reduce the number of synaptic inputs and thereby impair function.
doi:10.1007/s00455-008-9169-9
PMCID: PMC2644735  PMID: 18716837
deglutition; deglutition disorders; Sarcopenia; cranial motoneurons; genioglossus muscle; tongue; aging
16.  The Roles of the Actin Cytoskeleton in Fear Memory Formation 
The formation and storage of fear memory is needed to adapt behavior and avoid danger during subsequent fearful events. However, fear memory may also play a significant role in stress and anxiety disorders. When fear becomes disproportionate to that necessary to cope with a given stimulus, or begins to occur in inappropriate situations, a fear or anxiety disorder exists. Thus, the study of cellular and molecular mechanisms underpinning fear memory may shed light on the formation of memory and on anxiety and stress related disorders. Evidence indicates that fear learning leads to changes in neuronal synaptic transmission and morphology in brain areas underlying fear memory formation including the amygdala and hippocampus. The actin cytoskeleton has been shown to participate in these key neuronal processes. Recent findings show that the actin cytoskeleton is needed for fear memory formation and extinction. Moreover, the actin cytoskeleton is involved in synaptic plasticity and in neuronal morphogenesis in brain areas that mediate fear memory. The actin cytoskeleton may therefore mediate between synaptic transmission during fear learning and long-term cellular alterations mandatory for fear memory formation.
doi:10.3389/fnbeh.2011.00039
PMCID: PMC3139223  PMID: 21808614
actin cytoskeleton; fear memory; synaptic plasticity; amygdala; hippocampus
17.  Periadolescent ethanol exposure reduces adult forebrain ChAT+IR neurons: correlation with behavioral pathology 
Neuroscience  2011;199:333-345.
Substance abuse typically begins in adolescence; therefore, the impact of alcohol during this critical time in brain development is of particular importance. Epidemiological data indicate that excessive alcohol consumption is prevalent among adolescents and may have lasting neurobehavioral consequences. Loss of cholinergic input to the forebrain has been demonstrated following fetal alcohol exposure and in adults with Wernicke-Korsakoff syndrome. In the present study, immunohistochemistry for choline acetyltransferase (ChAT) was determined to assess forebrain cholinergic neurons (Ch1–4), and behavioral changes following periadolescent alcohol exposure. Wistar rats were exposed to intermittent ethanol vapor (14 hrs on/10 hrs off/day) for 35 days from PD 22-PD 57 (average blood alcohol concentration (BAC): 163 mg%). Rats were withdrawn from vapor and assessed for locomotor activity, startle response, conflict behavior in the open field, and immobility in the forced swim test, as adults. Rats were then sacrificed at day 71/72 and perfused for histochemical analyses. Ethanol vapor exposed rats displayed: increased locomotor activity 8 hrs after the termination of vapor delivery for that 24 hr period at day 10 and day 20 of alcohol vapor exposure, significant reductions in the amplitude of their responses to prepulse stimuli during the startle paradigm at 24 hrs withdrawal, and at two weeks following withdrawal, less anxiety-like and/or more “disinhibitory” behavior in the open field conflict, and more immobility in the forced swim test. Quantitative analyses of ChAT immunoreactivity revealed a significant reduction in cell counts in the Ch1–2 and Ch3–4 regions of the basal forebrain in ethanol vapor exposed rats. This reduction in cell counts was significantly correlated with less anxiety-like and/or more “disinhibitory” behavior in the open field conflict test. These studies demonstrate that behavioral measures of arousal, affective state, disinhibitory behavior and ChAT+IR, are all significantly impacted by periadolescent ethanol exposure and withdrawal in Wistar rats.
doi:10.1016/j.neuroscience.2011.10.011
PMCID: PMC3264427  PMID: 22033458
Adolescent; alcohol exposure; ChAT; forced swim test; open field conflict; startle
18.  Longitudinal 1H MR spectroscopy of rat forebrain from infancy to adulthood reveals adolescence as a distinctive phase of neurometabolite development 
NMR in biomedicine  2013;26(6):683-691.
The present study represents the first longitudinal, within-subject 1H MRS investigation of the developing rat brain spanning infancy, adolescence, and early adulthood. We obtained neurometabolite profiles from a voxel located in a central location of the forebrain, centered on the striatum, with smaller contributions for cortex, thalamus, and hypothalamus, on postnatal days 7, 35, and 60. Water-scaled metabolite signals were corrected for T1 effects and quantified using the automated processing software LCModel, yielding molal concentrations. Our findings indicate age-related concentration changes in N-acetylaspartate + N-acetylaspartylglutamate, myo-inositol, glutamate + glutamine, taurine, creatine + phosphocreatine, and glycerophosphocholine + phosphocholine. Using a repeated measures design and analysis, we identified significant neurodevelopment change across all three developmental ages and identified adolescence as a distinctive phase in normative neurometabolic brain development. Between postnatal days 35 and 60, changes were observed in concentrations of N-acetylaspartate + N-acetylaspartylglutamate, glutamate + glutamine, and glycerophosphocholine + phosphocholine observed between postnatal days 35 and 60. Our data replicate past studies of early neurometabolite development and, for the first time, link maturational profiles in the same subjects across infancy, adolescence, and adulthood.
doi:10.1002/nbm.2913
PMCID: PMC3634877  PMID: 23322706
MRS; adolescence; rat; development; brain; longitudinal; NMR; spectroscopy
19.  Social instability stress differentially affects amygdalar neuron adaptations and memory performance in adolescent and adult rats 
Adolescence is a time of developmental changes and reorganization in the brain. It has been hypothesized that stress has a greater neurological impact on adolescents than on adults. However, scientific evidence in support of this hypothesis is still limited. We treated adolescent (4-week-old) and adult (8-week-old) rats with social instability stress for 5 weeks and compared the subsequent structural and functional changes to amygdala neurons. In the stress-free control condition, the adolescent group showed higher fear-potentiated startle responses, larger dendritic arborization, more proximal dendritic spine distribution and lower levels of truncated TrkB than the adult rats. Social instability stress exerted opposite effects on fear-potentiated startle responses in these two groups, i.e., the stress period appeared to hamper the performance in adolescents but improved it in adult rats. Furthermore, whilst the chronic social stress applied to adolescent rats reduced their dendritic field and spine density in basal and lateral amygdala neurons, the opposite stress effects on neuron morphology were observed in the adult rats. Moreover, stress in adolescence suppressed the amygdala expression of synaptic proteins, i.e., full-length TrkB and SNAP-25, whereas, in the adult rats, chronic stress enhanced full-length and truncated TrkB expressions in the amygdala. In summary, chronic social instability stress hinders amygdala neuron development in the adolescent brain, while mature neurons in the amygdala are capable of adapting to the stress. The stress induced age-dependent effects on the fear-potentiated memory may occur by altering the brain-derived neurotrophic factor (BDNF)-TrkB signaling and neuroplasticity in the amygdala.
doi:10.3389/fnbeh.2014.00027
PMCID: PMC3909871  PMID: 24550802
adolescent; dendritic spine; memory; neuroplasticity; TrkB
20.  Microglial Activation & Chronic Neurodegeneration 
Microglia, the resident innate immune cells in the brain, have long been implicated in the pathology of neurodegenerative diseases. Accumulating evidence points to activated microglia as a chronic source of multiple neurotoxic factors, including TNFα, NO, IL1-β, and reactive oxygen species (ROS), driving progressive neuron damage. Microglia can become chronically activated by either a single stimulus (ex. LPS or neuron damage) or multiple stimuli exposures to result in cumulative neuronal loss over time. While the mechanisms driving these phenomena are just beginning to be understood, reactive microgliosis (the microglial response to neuron damage) and ROS have been implicated as key mechanisms of chronic and neurotoxic microglial activation, particularly in the case of Parkinson’s Disease. Here, we review the mechanisms of neurotoxicity associated with chronic microglial activation and discuss the role of neuronal death and microglial ROS driving the chronic and toxic microglial phenotype.
doi:10.1016/j.nurt.2010.05.014
PMCID: PMC2951017  PMID: 20880500
Microglia; inflammation-mediated neurodegeneration; oxidative stress; chronic neurotoxicity; reactive microgliosis
21.  Neuron and glia numbers in the basolateral nucleus of the amygdala from preweaning through old age in male and female rats 
The rat basolateral nucleus of the amygdala continues to develop connectivity with the frontal cortex through the periadolescent period and even into young adulthood. Although neuronal loss in the prefrontal cortex has been found during the periadolescent period, prior literature has not examined whether neuron number in the basolateral amygdala is stable through this period. In addition, aging of the rat basolateral nucleus is accompanied by significant increases in the dendritic tree of its principal neurons, but whether this occurs in the context of neuronal death has not been previously explored. In the present study, a stereological examination of neuron and glia numbers in the rat basolateral amygdalar nucleus was undertaken in male and female hooded rats at one of four ages across the lifespan. Our findings indicate (1) a significant decrease in the number of neurons and glia in the basolateral nucleus between adolescence and adulthood, and (2) the number of glia, as well as the volume of the basolateral nucleus, increase between adulthood and old age, while neuron number remains stable. These findings provide an important cellular context for interpretation of the neurochemical and other alterations documented in developmental and age-related literature on the rat basolateral amygdala, and underline the substantial development of this brain area during adolescence, as well as its comparative preservation during aging.
doi:10.1002/cne.21924
PMCID: PMC2647367  PMID: 19065620
basolateral amygdala; stereology; development; adolescence; aging; sex differences
22.  Anti-Müllerian hormone may regulate the number of calbindin-positive neurons in the sexually dimorphic nucleus of the preoptic area of male mice 
Background
The male brain is putatively organised early in development by testosterone, with the sexually dimorphic nucleus of the medial preoptic area (SDN) a main exemplifier of this. However, pubescent neurogenesis occurs in the rat SDN, and the immature testes secrete anti-Müllerian hormone (AMH) as well as testosterone. We have therefore re-examined the development of the murine SDN to determine whether it is influenced by AMH and/or whether the number of calbindin-positive (calbindin+ve) neurons in it changes after pre-pubescent development.
Methods
In mice, the SDN nucleus is defined by calbindin+ve neurons (CALB-SDN). The number and size of the neurons in the CALB-SDN of male and female AMH null mutant (Amh-/-) mice and their wild-type littermates (Amh+/+) were studied using stereological techniques. Groups of mice were examined immediately before the onset of puberty (20 days postnatal) and at adulthood (129–147 days old).
Results
The wild-type pre-pubertal male mice had 47% more calbindin+ve neurons in the CALB-SDN than their female wild-type littermates. This sex difference was entirely absent in Amh-/- mice. In adults, the extent of sexual dimorphism almost doubled due to a net reduction in the number and size of calbindin+ve neurons in females and a net increase in neuron number in males. These changes occurred to a similar extent in the Amh-/- and Amh+/+ mice. Consequently, the number of calbindin+ve neurons in Amh-/- adult male mice was intermediate between Amh+/+ males and Amh+/+ females. The sex difference in the size of the neurons was predominantly generated by a female-specific atrophy after 20 days, independent of AMH.
Conclusions
The establishment of dimorphic cell number in the CALB-SDN of mice is biphasic, with each phase being subject to different regulation. The second phase of dimorphism is not dependent on the first phase having occurred as it was present in the Amh-/- male mice that have female-like numbers of calbindin+ve neurons at 20 days. These observations extend emerging evidence that the organisation of highly dimorphic neuronal networks changes during puberty or afterwards. They also raise the possibility that cellular events attributed to the imprinting effects of testosterone are mediated by AMH.
doi:10.1186/2042-6410-4-18
PMCID: PMC3852321  PMID: 24119315
Sexual dimorphic nucleus; Anti-Müllerian hormone; Puberty; Development; Childhood; Calbindin; Medial preoptic area; Imprinting
23.  The Neurodevelopmental Hypothesis of Schizophrenia, Revisited 
Schizophrenia Bulletin  2009;35(3):528-548.
While multiple theories have been put forth regarding the origin of schizophrenia, by far the vast majority of evidence points to the neurodevelopmental model in which developmental insults as early as late first or early second trimester lead to the activation of pathologic neural circuits during adolescence or young adulthood leading to the emergence of positive or negative symptoms. In this report, we examine the evidence from brain pathology (enlargement of the cerebroventricular system, changes in gray and white matters, and abnormal laminar organization), genetics (changes in the normal expression of proteins that are involved in early migration of neurons and glia, cell proliferation, axonal outgrowth, synaptogenesis, and apoptosis), environmental factors (increased frequency of obstetric complications and increased rates of schizophrenic births due to prenatal viral or bacterial infections), and gene-environmental interactions (a disproportionate number of schizophrenia candidate genes are regulated by hypoxia, microdeletions and microduplications, the overrepresentation of pathogen-related genes among schizophrenia candidate genes) in support of the neurodevelopmental model. We relate the neurodevelopmental model to a number of findings about schizophrenia. Finally, we also examine alternate explanations of the origin of schizophrenia including the neurodegenerative model.
doi:10.1093/schbul/sbn187
PMCID: PMC2669580  PMID: 19223657
brain; genes; animal model; pathology; epidemiology; antiviral model; schizophrenia
24.  Quantification of Brain Maturation and Growth Patterns in C57BL/6J Mice via Computational Neuroanatomy of Diffusion Tensor Images 
Cerebral Cortex (New York, NY)  2008;19(3):675-687.
Diffusion Tensor magnetic resonance imaging and computational neuroanatomy are used to quantify postnatal developmental patterns of C57BL/6J mouse brain. Changes in neuronal organization and myelination occurring as the brain matures into adulthood are examined, and a normative baseline is developed, against which transgenic mice may be compared in genotype–phenotype studies. In early postnatal days, gray matter–based cortical and hippocampal structures exhibit high water diffusion anisotropy, presumably reflecting the radial neuronal organization. Anisotropy drops rapidly within a week, indicating that the underlying brain tissue becomes more isotropic in orientation, possibly due to formation of a complex randomly intertwined web of dendrites. Gradual white matter anisotropy increase implies progressively more organized axonal pathways, likely reflecting the myelination of axons forming tightly packed fiber bundles. In contrast to the spatially complex pattern of tissue maturation, volumetric growth is somewhat uniform, with the cortex and the cerebellum exhibiting slightly more pronounced growth. Temporally, structural growth rates demonstrate an initial rapid volumetric increase in most structures, gradually tapering off to a steady state by about 20 days. Fiber maturation reaches steady state in about 10 days for the cortex, to 30–40 days for the corpus callosum, the hippocampus, and the internal and external capsules.
doi:10.1093/cercor/bhn112
PMCID: PMC3140198  PMID: 18653668
computational neuroanatomy; development atlas; diffusion tensor imaging; fractional anisotropy; mouse brain
25.  Three counting methods agree on cell and neuron number in chimpanzee primary visual cortex 
Determining the cellular composition of specific brain regions is crucial to our understanding of the function of neurobiological systems. It is therefore useful to identify the extent to which different methods agree when estimating the same properties of brain circuitry. In this study, we estimated the number of neuronal and non-neuronal cells in the primary visual cortex (area 17 or V1) of both hemispheres from a single chimpanzee. Specifically, we processed samples distributed across V1 of the right hemisphere after cortex was flattened into a sheet using two variations of the isotropic fractionator cell and neuron counting method. We processed the left hemisphere as serial brain slices for stereological investigation. The goal of this study was to evaluate the agreement between these methods in the most direct manner possible by comparing estimates of cell density across one brain region of interest in a single individual. In our hands, these methods produced similar estimates of the total cellular population (approximately 1 billion) as well as the number of neurons (approximately 675 million) in chimpanzee V1, providing evidence that both techniques estimate the same parameters of interest. In addition, our results indicate the strengths of each distinct tissue preparation procedure, highlighting the importance of attention to anatomical detail. In summary, we found that the isotropic fractionator and the stereological optical fractionator produced concordant estimates of the cellular composition of V1, and that this result supports the conclusion that chimpanzees conform to the primate pattern of exceptionally high packing density in V1. Ultimately, our data suggest that investigators can optimize their experimental approach by using any of these counting methods to obtain reliable cell and neuron counts.
doi:10.3389/fnana.2014.00036
PMCID: PMC4032965  PMID: 24904305
stereology; isotropic fractionator; flow cytometry; cell density; neuron number

Results 1-25 (1008574)