Development of the motivational system during adolescence, and its sensitivity to disruption by nicotine

The brain continues to develop during adolescence, and exposure to exogenous substances such as nicotine can exert long-lasting adaptations during this vulnerable period. In order to fully understand how nicotine affects the adolescent brain it is important to understand normal adolescent brain development. This review summarizes human and animal data on brain development, with emphasis on the prefrontal cortex, for its important function in executive control over behavior. Moreover, we discuss how nicotine exposure during adolescence can disrupt brain development bearing long-term consequences on executive cognitive function in adulthood.     

The development of the ventral prefrontal cortex and social flexibility

Over the last several years a number of studies in both humans and animals have suggested that the orbitofrontal and ventrolateral prefrontal cortices play an important role in generating flexible behavior. We suggest that input from these brain regions contribute to three functions involved in generating flexible behavior within social contexts: valuation, inhibition, and rule use. Recent studies have also demonstrated that the prefrontal cortex undergoes a prolonged course of maturation that extends well after puberty. Here, we review evidence that the prolonged development of these prefrontal regions parallels a slowly emerging ability for flexible social behavior. We also speculate on the possibility that sensitive periods for organizing social behavior may be embedded within this developmental time-fame. Finally, we discuss the role of prefrontal cortex in adolescent mood and anxiety disorders, particularly as orbitofrontal and ventrolateral prefrontal cortices are engaged in a social context.     

Differential expression of cytoskeletal regulatory factors in the adolescent prefrontal cortex: Implications for cortical development

The prevalence of depression, anxiety, schizophrenia, and drug and alcohol use disorders peaks during adolescence. Further, up to 50% of “adult” mental health disorders emerge in adolescence. During adolescence, the prefrontal cortex (PFC) undergoes dramatic structural reorganization, in which dendritic spines and synapses are refined, pruned, and stabilized. Understanding the molecular mechanisms that underlie these processes should help to identify factors that influence the development of psychiatric illness. Here we briefly discuss the anatomical connections of the medial and orbital prefrontal cortex (mPFC and OFC, respectively). We then present original findings suggesting that dendritic spines on deep‐layer excitatory neurons in the mouse mPFC and OFC prune at different adolescent ages, with later pruning in the OFC. In parallel, we used Western blotting to define levels of several cytoskeletal regulatory proteins during early, mid‐, and late adolescence, focusing on tropomyosin‐related kinase receptor B (TrkB) and β1‐integrin–containing receptors and select signaling partners. We identified regional differences in the levels of several proteins in early and midadolescence that then converged in early adulthood. We also observed age‐related differences in TrkB levels, both full‐length and truncated isoforms, Rho‐kinase 2, and synaptophysin in both PFC subregions. Finally, we identified changes in protein levels in the dorsal and ventral hippocampus that were distinct from those in the PFC. We conclude with a general review of the manner in which TrkB‐ and β1‐integrin–mediated signaling influences neuronal structure in the postnatal brain. Elucidating the role of cytoskeletal regulatory factors throughout adolescence may identify critical mechanisms of PFC development. © 2016 Wiley Periodicals, Inc.     

Pattern of neural activation following yohimbine‐induced reinstatement of alcohol seeking in rats

Alcohol use disorders represent an extensive socioeconomic burden, yet effective treatment options are suboptimal. A major hurdle in treating alcohol use disorders is the high rate of relapse. Stress is a major factor that promotes relapse in abstinent drug users; therefore, understanding neural mechanisms that underpin the effects of stress on alcohol seeking is critical. In rodent models of stress‐induced relapse, the α₂‐adrenoceptor antagonist, yohimbine, is a widely used chemical stressor to elicit reinstatement of drug/alcohol seeking. However, the exact mechanism how yohimbine precipitates reinstatement of alcohol seeking and the pattern of neural activation associated with yohimbine‐induced reinstatement is poorly understood. Therefore, we counted Fos‐protein positive nuclei across 42 brain regions in alcohol‐experienced alcohol preferring rats that received either yohimbine in the home‐cage (1 mg/kg i.p.) or following yohimbine‐induced reinstatement of alcohol seeking. The number of Fos‐protein positive nuclei was increased in the prefrontal cortex and extended amygdala after home‐cage yohimbine compared to naïve‐ and vehicle‐treated rats. Yohimbine‐induced reinstatement increased the number of Fos‐protein expressing nuclei in multiple other regions including the thalamus, hypothalamus and hippocampus. We then examined inter‐regional correlations in Fos‐protein expression for all 42 brain regions, which showed Fos expression was more strongly positively correlated following yohimbine‐induced reinstatement of alcohol seeking, compared to home‐cage yohimbine. These data suggest low‐dose yohimbine in a non‐drug‐associated context activates stress/impulsivity centres within the brain, whereas yohimbine in the drug‐associated context recruits additional brain regions to drive alcohol seeking.     

Role of the innate immune system in the neuropathological consequences induced by adolescent binge drinking

Adolescence is a critical stage of brain maturation in which important plastic and dynamic processes take place in different brain regions, leading to development of the adult brain. Ethanol drinking in adolescence disrupts brain plasticity and causes structural and functional changes in immature brain areas (prefrontal cortex, limbic system) that result in cognitive and behavioral deficits. These changes, along with secretion of sexual and stress‐related hormones in adolescence, may impact self‐control, decision making, and risk‐taking behaviors that contribute to anxiety and initiation of alcohol consumption. New data support the participation of the neuroimmune system in the effects of ethanol on the developing and adult brain. This article reviews the potential pathological bases that underlie the effects of alcohol on the adolescent brain, such as the contribution of genetic background, the perturbation of epigenetic programming, and the influence of the neuroimmune response. Special emphasis is given to the actions of ethanol in the innate immune receptor toll‐like receptor 4 (TLR4), since recent studies have demonstrated that by activating the inflammatory TLR4/NFκB signaling response in glial cells, binge drinking of ethanol triggers the release of cytokines/chemokines and free radicals, which exacerbate the immune response that causes neuroinflammation/neural damage as well as short‐ and long‐term neurophysiological, cognitive, and behavioral dysfunction. Finally, potential treatments that target the neuroimmune response to treat the neuropathological and behavioral consequences of adolescent alcohol abuse are discussed.     

Adolescent nicotine induces persisting changes in development of neural connectivity

Adolescent nicotine induces persisting changes in development of neural connectivity. A large number of brain changes occur during adolescence as the CNS matures. These changes suggest that the adolescent brain may still be susceptible to developmental alterations by substances which impact its growth. Here we review recent studies on adolescent nicotine which show that the adolescent brain is differentially sensitive to nicotine-induced alterations in dendritic elaboration, in several brain areas associated with processing reinforcement and emotion, specifically including nucleus accumbens, medial prefrontal cortex, basolateral amygdala, bed nucleus of the stria terminalis, and dentate gyrus. Both sensitivity to nicotine, and specific areas responding to nicotine, differ between adolescent and adult rats, and dendritic changes in response to adolescent nicotine persist into adulthood. Areas sensitive to, and not sensitive to, structural remodeling induced by adolescent nicotine suggest that the remodeling generally corresponds to the extended amygdala. Evidence suggests that dendritic remodeling is accompanied by persisting changes in synaptic connectivity. Modeling, electrophysiological, neurochemical, and behavioral data are consistent with the implication of our anatomical studies showing that adolescent nicotine induces persisting changes in neural connectivity. Emerging data thus suggest that early adolescence is a period when nicotine consumption, presumably mediated by nicotine-elicited changes in patterns of synaptic activity, can sculpt late brain development, with consequent effects on synaptic interconnection patterns and behavior regulation. Adolescent nicotine may induce a more addiction-prone phenotype, and the structures altered by nicotine also subserve some emotional and cognitive functions, which may also be altered. We suggest that dendritic elaboration and associated changes are mediated by activity-dependent synaptogenesis, acting in part through D1DR receptors, in a network activated by nicotine. The adolescent nicotine effects reviewed here suggest that modification of late CNS development constitutes a hazard of adolescent nicotine use.     

Synaptic number changes in the medial prefrontal cortex across adolescence in male and female rats: A role for pubertal onset

Adolescence is a unique period of development, marked by maturation of the prefrontal cortex (PFC), a region important for executive functioning. During this time, the human PFC decreases in overall volume and thickness. Likewise in adolescent rodents, losses of neurons, dendrites, dendritic spines and neurotransmitter receptors have been documented within the medial prefrontal cortex (mPFC), sometimes with sex and layer specificity. However, changes in the number of synapses during this time have not been examined. In the present study, we stereologically quantified the number of synaptophysin‐immunoreactive boutons in the male and female rat mPFC across multiple time points from the juvenile period through adulthood (postnatal days (P) 25, 35, 45, 60 and 90). In females, there was a significant decrease in synaptophysin boutons between P35 and P45, coinciding with the onset of puberty. In males, there was no significant main effect of age on synaptophysin boutons; however, in both males and females, pubertal onset was associated with significant synaptic losses. These results suggest that puberty is a critical period for synaptic pruning within the rat mPFC, potentially contributing to maturation of adolescent executive function. Synapse 70:361–368, 2016 . © 2016 Wiley Periodicals, Inc.     

Life stress in adolescence predicts early adult reward-related brain function and alcohol dependence

Stressful life events increase vulnerability to problematic alcohol use, and they may do this by disrupting reward-related neural circuitry. This is particularly relevant for adolescents because alcohol use rises sharply after mid-adolescence and alcohol abuse peaks at age 20. Adolescents also report more stressors compared with children, and neural reward circuitry may be especially vulnerable to stressors during adolescence because of prefrontal cortex remodeling. Using a large sample of male participants in a longitudinal functional magnetic resonance imaging study (N = 157), we evaluated whether cumulative stressful life events between the ages of 15 and 18 were associated with reward-related brain function and problematic alcohol use at age 20 years. Higher cumulative stressful life events during adolescence were associated with decreased response in the medial prefrontal cortex (mPFC) during monetary reward anticipation and following the receipt of monetary rewards. Stress-related decreases in mPFC response during reward anticipation and following rewarding outcomes were associated with the severity of alcohol dependence. Furthermore, mPFC response mediated the association between stressful life events and later symptoms of alcohol dependence. These data are consistent with neurobiological models of addiction that propose that stressors during adolescence increase risk for problematic alcohol use by disrupting reward circuit function.     

Hippocampal and prefrontal contributions to memory retrieval: Examination of immediate early gene,NMDA receptor and environmental interactions

Animals can use a range of strategies to recall important locations. These include simple stimulus–response strategies and more complex spatial (place) strategies, which are thought to have distinct neural substrates. The hippocampus—and NMDA receptor activation therein—is considered to be crucial for spatial, but not response strategies. The medial prefrontal cortex has also been implicated in memory retrieval; however, evidence concerning its specific role is equivocal. Both hippocampal and prefrontal regions have been associated with flexible behavioural responding (e.g. when task demands change). Here, we investigated the use of spatial and non‐spatial strategies in the Morris water maze and their associated brain areas in rats using immediate early gene (IEG) imaging of Zif268 and c‐Fos. Specifically, we charted the involvement of hippocampal and prefrontal subregions during retrieval of spatial and non‐spatial memories. Behavioural flexibility was also examined using intact and partial cue configurations during recall. Results indicated that regions of both the hippocampus (area CA3) and prefrontal cortex (anterior cingulate cortex) were preferentially engaged in spatial memory recall compared to response learning. In addition, both spatial and non‐spatial memories were dependent on NMDA receptor activation. MK801 impaired recall performance across all groups and reduced IEG activation across hippocampal and prefrontal regions. Finally, IEG results revealed divergent patterns of Zif268 and c‐Fos activity and support the suggestion that Zif268 plays a functional role in the recall of long‐term memories.     

Prenatal exposure to alcohol impairs social play behavior in adolescent male mice

Prenatal ethanol exposure affects brain development and causes neural impairment, leading to both cognitive and behavioral consequences in the offspring. Therefore, the aim of this study was to investigate the impact of prenatal exposure to small amounts of alcohol on social play behavior in adolescent male offspring. Swiss mice were prenatally exposed to ethanol by feeding pregnant dams with a liquid diet containing 25% alcohol-derived calories during gestation (alcohol group). They were then compared to both pair-fed dams that received an isocaloric liquid diet containing 0% alcohol-derived calories (pair-fed group) and dams with ad libitum access to a liquid control diet (control group). Additionally, maternal behavior was evaluated in terms of neural activation indexed via c-fos expression in the prefrontal cortex. Although dams exposed to alcohol during pregnancy did not alter their maternal behavior, the offspring presented a decrease in their social play behavior compared with both control and pair-fed offspring. The decrease in social play behavior may be associated with a decrease in number of c-fos-positive cells in the prefrontal cortex. The exposure to small amounts of alcohol during intrauterine development causes both a deficit in social play behavior and a reduction in the neuronal activity seen in the prefrontal cortex.     

Peer facilitation of emotion regulation in adolescence

Emotion regulation is particularly important for adolescents as they undergo normative developmental changes in affective systems and experience heightened risk for psychopathology. Despite a high need for emotion regulation during adolescence, commonly studied emotion regulation strategies like cognitive reappraisal are less beneficial for adolescents than adults because they rely on neural regions that are still developing during this period (i.e., lateral prefrontal cortex). However, adolescence is also marked by increased valuation of peer relationships and sensitivity to social information and cues. In the present review, we synthesize research examining emotion regulation and peer influence across development to suggest that sensitivity to peers during adolescence could be leveraged to improve emotion regulation for this population. We first discuss developmental trends related to emotion regulation at the level of behavior and brain in adolescents, using cognitive reappraisal as an exemplar emotion regulation strategy. Next, we discuss social influences on adolescent brain development, describing caregiver influence and increasing susceptibility to peer influence, to describe how adolescent sensitivity to social inputs represents both a window of vulnerability and opportunity. Finally, we conclude by describing the promise of social (i.e., peer-based) interventions for enhancing emotion regulation in adolescence.     

Adolescent anxiety disorders and the developing brain: comparing neuroimaging findings in adolescents and adults

Adolescence is the peak period for the incidence of anxiety disorders. Recent findings have revealed the immaturity of neural networks underlying emotional regulation in this population. Brain vulnerability to anxiety in adolescence is related to the unsynchronised development of anxiety-relevant brain functional systems. However, our current knowledge on brain deficits in adolescent anxiety is mainly borrowed from studies on adults. Understanding adolescent-specific brain deficits is essential for developing biomarkers and brain-based therapies targeting adolescent anxiety. This article reviews and compares recent neuroimaging literature on anxiety-related brain structural and functional deficits between adolescent and adult populations, and proposes a model highlighting the differences between adolescence and adulthood in anxiety-related brain networks. This model emphasises that in adolescence the emotional control system tends to be hypoactivated, the fear conditioning system is immature, and the reward and stress response systems are hypersensitive. Furthermore, the striatum’s functional links to the amygdala and the prefrontal cortex are strengthened, while the link between the prefrontal cortex and the amygdala is weakened in adolescence. This model helps to explain why adolescents are vulnerable to anxiety disorders and provides insights into potential brain-based approaches to intervene in adolescent anxiety disorders.     

The maternal brain under stress: Consequences for adaptive peripartum plasticity and its potential functional implications

The peripartum period represents a time during which all mammalian species undergo substantial physiological and behavioural changes, which prepare the female for the demands of motherhood. In addition to behavioural and physiological alterations, numerous brain regions, such as the medial prefrontal cortex, olfactory bulb, medial amygdala and hippocampus are subject to substantial peripartum-associated neuronal, dendritic and synaptic plasticity. These changes, which are temporally- and spatially-distinct, are strongly influenced by gonadal and adrenal hormones, such as estrogen and cortisol/corticosterone, which undergo dramatic fluctuations across this period. In this review, we describe our current knowledge regarding these plasticity changes and describe how stress affects such normal adaptations. Finally, we discuss the mechanisms potentially underlying these neuronal, dendritic and synaptic changes and their functional relevance for the mother and her offspring.     

Higher GABA concentration in the medial prefrontal cortex of Type 2 diabetes patients is associated with episodic memory dysfunction

Type 2 diabetes (T2D) is associated with an accelerated episodic memory decline, but the underlying pathophysiological mechanisms are not well understood. Hallmarks of T2D comprise impairment of insulin secretion and insulin sensitivity. Insulin signaling modulates cerebral neurotransmitter activity, including the excitatory glutamate and inhibitory gamma‐aminobutyric acid (GABA) systems. Here we tested the hypothesis that the glutamate and GABA systems are altered in T2D patients and this relates to memory decline and insulin resistance. Using ¹H‐magnetic resonance spectroscopy (MRS), we examined glutamate and GABA concentrations in episodic memory relevant brain regions (medial prefrontal cortex and precuneus) of T2D patients and matched controls. Insulin sensitivity was measured by hyperinsulinemic‐euglycemic clamps and memory performance was assessed using a face‐profession associations test. T2D patients exhibited peripheral insulin resistance and had a decreased memory for face‐profession associations as well as elevated GABA concentration in the medial prefrontal cortex but not precuneus. In addition, medial prefrontal cortex GABA concentration was negatively associated with memory performance suggesting that abnormal GABA levels in the medial prefrontal cortex are linked to the episodic memory decline that occurs in T2D patients.     

Adolescent social isolation influences cognitive function in adult rats

Adolescence is a critical period for neurodevelopment. Evidence from animal studies suggests that isolated rearing can exert negative effects on behavioral and brain development. The present study aimed to investigate the effects of adolescent social isolation on latent inhibition and brain-derived neurotrophic factor levels in the forebrain of adult rats. Male Wistar rats were randomly divided into adolescent isolation (isolated housing, 38-51 days of age) and social groups. Latent inhibition was tested at adulthood. Brain-derived neurotrophic factor levels were measured in the medial prefrontal cortex and nucleus accumbens by an enzyme-linked immunosorbent assay. Adolescent social isolation impaired latent inhibition and increased brain-derived neurotrophic factor levels in the medial prefrontal cortex of young adult rats. These data suggest that adolescent social isolation has a profound effect on cognitive function and neurotrophin levels in adult rats and may be used as an animal model of neurodevelopmental disorders.     

Antipsychotic drug interactions with specific [3H]ketanserin binding sites in membrane fragments derived from human prefrontal cortex and human amygdala

Two regions of the brain potentially significant for psychopathology in schizophrenia are the prefrontal cortex and the amygdala. Antipsychotic compounds bind at serotonin receptors in human prefrontal cortex. We hypothesized that the serotoninergic antagonist [3H]ketanserin would label similar sets of binding sites in these two brain regions. Further, we hypothesized that all antipsychotic compounds would show appreciable affinity for binding sites labeled by [3H]ketanserin in the prefrontal cortex. Our findings indicate some differences in [3H]ketanserin binding between prefrontal cortex and amygdala. We also observed that several antipsychotic compounds had very high affinity for the [3H]ketanserin binding sites in prefrontal cortex.     

Hypofrontality in attention deficit hyperactivity disorder during higher-order motor control: a study with functional MRI.

OBJECTIVE: Functional magnetic resonance imaging (MRI) was used to investigate the hypothesis that attention deficit hyperactivity disorder (ADHD) is associated with a dysfunction of prefrontal brain regions during motor response inhibition and motor timing. METHOD: Generic brain activation of seven adolescent boys with ADHD was compared to that of nine comparison subjects equivalent in sex, age, and IQ while they were performing a stop task, requiring inhibition of a planned motor response, and a motor timing task, requiring timing of a motor response to a sensory cue. RESULTS: The hyperactive adolescents showed lower power of response in the right mesial prefrontal cortex during both tasks and in the right inferior prefrontal cortex and left caudate during the stop task. CONCLUSIONS: ADHD is associated with subnormal activation of the prefrontal systems responsible for higher-order motor control. Functional MRI is a feasible technique for investigation of neural correlates of ADHD.     

Serotonin receptor, SERT mRNA and correlations with symptoms in males with alcohol dependence and suicide

Thompson PM, Cruz DA, Olukotun DY, Delgado PL. Serotonin receptor, SERT mRNA and correlations with symptoms in males with alcohol dependence and suicide. Objective: This study tested the hypothesis that abnormalities in components of the serotonin (5HT) system in the prefrontal cortex are associated with suicide in alcohol‐dependent subjects. Second, we assessed the relationship of lifetime impulsivity and mood symptoms with prefrontal cortex 5‐HT measures. Method: Tissue was obtained from Brodmann’s areas (BA) 9 and 24 in postmortem samples of individuals who were alcohol dependent with suicide (n = 5), alcohol dependent without suicide (n = 9) and normal controls (n = 5). Serotonin receptor (5HT) and serotonin reuptake transporter (SERT) mRNA were measured. Interviews with next of kin estimated lifetime impulsivity and mood symptoms in the last week of life. Results: Serotonin receptor 1A (5HT1A) mRNA in BA 9 was elevated in the alcohol dependence without suicide group compared with controls. In the alcohol dependence with suicide group, anxiety symptoms were associated with decreased BA 24 SERT mRNA and depressive symptoms with BA 9 5HT1A mRNA expression. In the alcohol dependent only group impulsivity is correlated with increased BA 9, and BA 24 serotonin receptor 2A mRNA. Conclusion: Our data suggest region‐specific change, rather than global serotonin blunting is involved in alcohol dependence and suicide. It also suggests that symptoms are differentially influenced by prefrontal cortex serotonin receptor mRNA levels.     

Chronic nicotine doses down-regulate PDE4 isoforms that are targets of antidepressants in adolescent female rats.

BACKGROUND: Previous data in humans and animal models has suggested connections between anxiety, depression, smoking behavior, and nicotine dependence. The importance of these connections has been confirmed by clinical studies that led to the recent FDA approval of an anti-depressant (Zyban) for use in human smoking cessation programs. Other anti-depressants (such as rolipram) specifically inhibit PDE4 phosphodiesterases. METHODS: We used DNA microarrays to discover gene expression changes in adolescent female rats following chronic nicotine treatments, and real-time PCR assays to confirm and extend those results. RESULTS: We found a consistent decrease in the mRNA levels encoded by the Pde4b gene in nucleus accumbens, prefrontal cortex, and hippocampus of adolescent female rats treated with .24 mg/day nicotine, and in prefrontal cortex of adolescent female rats treated with .12 mg/day nicotine. We further show that each of these brain areas produced a different profile of Pde4b isoforms. CONCLUSIONS: Chronic nicotine treatments produce a dose-dependent down-regulation of Pde4b, which may have an antidepressant effect. This is the first report of a link between nicotine dependence and phosphodiesterase gene expression. Our results also add to the complex interrelationships between smoking and schizophrenia, because mutations in the PDE4B gene are associated with schizophrenia.