Exposure to cocaine and amphetamine structurally reorganizes excitatory neurons in the medial and orbital prefrontal cortices (mPFC and oPFC), inducing dendritic spine proliferation in the mPFC and eliminating spines in the oPFC. Modifications may be causally associated with addiction etiology. Certain cytoskeletal regulatory proteins expressed in the oPFC and implicated in postnatal neural development also regulate behavioral sensitivity to cocaine, potentially opening a window of opportunity for the identification of novel pharmacotherapeutic targets in the treatment of drug abuse disorders. Addiction is characterized by maladaptive decision-making, a loss of control over drug consumption and habit-like drug seeking despite adverse consequences. These cognitive changes may reflect the effects of drugs of abuse on prefrontal cortical neurobiology. Here, we review evidence that amphetamine and cocaine fundamentally remodel the structure of excitatory neurons in the prefrontal cortex. We summarize evidence in particular that these psychostimulants have opposing effects in the medial and orbital prefrontal cortices ('mPFC' and 'oPFC', respectively). For example, amphetamine and cocaine increase dendrite length and spine density in the mPFC, while dendrites are impoverished and dendritic spines are eliminated in the oPFC. We will discuss evidence that certain cytoskeletal regulatory proteins expressed in the oPFC and implicated in postnatal (adolescent) neural development also regulate behavioral sensitivity to cocaine. These findings potentially open a window of opportunity for the identification of novel pharmacotherapeutic targets in the treatment of drug abuse disorders in adults, as well as in drug-vulnerable adolescent populations. Finally, we will discuss the behavioral implications of drug-related dendritic spine elimination in the oPFC, with regard to reversal learning tasks and tasks that assess the development of reward-seeking habits, both used to model aspects of addiction in rodents.
We recently reported that prolonged exposure to the glucocorticoid receptor (GR) ligand corticosterone impairs decision-making that is dependent on the predictive relationship between an action and its outcome (Gourley et al.; Proceedings of the National Academy of Sciences, 2012). Additionally, acute GR blockade, when paired with action-outcome conditioning, also blocks new learning. We then showed that dendritic spines in the prelimbic prefrontal cortex remodeled under both conditions. Nonetheless, the relationship between deep-layer dendritic spines and outcome-based decision-making remains opaque. We report here that a history of prolonged corticosterone exposure increases dendritic spine density in deep-layer prelimbic cortex. When spines are imaged simultaneously with corticosteroid exposure (i.e., without a washout period), dendritic spine densities are, however, reduced. Thus, the morphological response of deep-layer prelimbic cortical neurons to prolonged corticosteroid exposure may be quite dynamic, with spine elimination during a period of chronic exposure and spine proliferation during a subsequent washout period. We provide evidence, using a Rho-kinase inhibitor, that GR-mediated dendritic spine remodeling is causally related to complex decision-making. Finally, we conclude this report with evidence that a history of early-life (adolescent) GR blockade, unlike acute blockade in adulthood, enhances subsequent outcome-based decision-making. Together, our findings suggest that physiological levels of GR binding enable an organism to learn about the predictive relationship between an action and its outcome, but a history of GR blockade may, under some circumstances, also have beneficial consequences.
The gold-standard measure of tic severity in tic disorders (TD), the Yale Global Tic Severity Scale (YGTSS), is a semistructured clinician-administered interview that can be time consuming and requires highly trained interviewers. Moreover, the YGTSS does not provide information regarding frequency and intensity of specific tics because all motor and all vocal tics are rated as a group. The aim of the present study is to describe and test the Adult Tic Questionnaire (ATQ), a measure for the assessment of tic severity in adults, and to report its preliminary psychometric properties. The ATQ is a brief self-report questionnaire that provides information regarding frequency, intensity, and severity of 27 specific tics. In addition, the ATQ produces total frequency, intensity, and severity scores for vocal and motor tics, as well as a global total tic severity score. Results showed that the ATQ demonstrated very good internal consistency and temporal stability. The total, vocal, and motor tic severity scales of the ATQ showed strong correlation with corresponding subscales of the YGTSS, indicating strong convergent validity. Weak correlations with measures of severity of obsessive-compulsive disorder and attention deficit/hyperactivity disorder, indicated strong discriminant validity. The ATQ, a promising measure for the assessment of tic severity in adults with TD, may be a valuable supplement to the current recommended assessment battery for TD. Furthermore, the ATQ enables clinicians and researchers to track changes in the frequency and intensity of specific tics, which is important given their complex and dynamic nature.
In humans and rodents, stress promotes habit-based behaviors that can interfere with action—outcome decision-making. Further, developmental stressor exposure confers long-term habit biases across rodent—primate species. Despite these homologies, mechanisms remain unclear. We first report that exposure to the primary glucocorticoid corticosterone (CORT) in adolescent mice recapitulates multiple neurobehavioral consequences of stressor exposure, including long-lasting biases towards habit-based responding in a food-reinforced operant conditioning task. In both adolescents and adults, CORT also caused a shift in the balance between full-length tyrosine kinase receptor B (trkB) and a truncated form of this neurotrophin receptor, favoring the inactive form throughout multiple corticolimbic brain regions. In adolescents, phosphorylation of the trkB substrate extracellular signal-regulated kinase 42/44 (ERK42/44) in the ventral hippocampus was also diminished, a long-term effect that persisted for at least 12 wk. Administration of the trkB agonist 7,8-dihydroxyflavone (7,8-DHF) during adolescence at doses that stimulated ERK42/44 corrected long-lasting corticosterone-induced behavioral abnormalities. Meanwhile, viral-mediated overexpression of truncated trkB in the ventral hippocampus reduced local ERK42/44 phosphorylation and was sufficient to induce habit-based and depression-like behaviors. Together, our findings indicate that ventral hippocampal trkB is essential to goal-directed action selection, countering habit-based behavior otherwise facilitated by developmental stress hormone exposure. They also reveal an early-life sensitive period during which trkB—ERK42/44 tone determines long-term behavioral outcomes.
Stressor exposure causes dendritic remodeling on excitatory neurons in multiple regions of the brain, including the orbitofrontal cortex (OFC). Additionally, stressor and exogenous stress hormone exposure impair cognitive functions that are dependent on the OFC. For this Special Issue on the OFC, we summarize current literature regarding how stress—prenatal, postnatal, and even inter-generational—affects OFC neuron structure in rodents. We discuss dendrite structure, dendritic spines, and gene expression. We aim to provide a focused resource for those interested in how stressors impact this heterogeneous brain region. (PsycInfo Database Record (c) 2021 APA, all rights reserved)
Prefrontal cortical dendritic spine remodeling during adolescence may open a window of vulnerability to pathological stimuli that impact long-term behavioral outcomes, but causal mechanisms remain unclear. We administered the Rho-kinase inhibitor HA-1077 during three adolescent periods in mice to destabilize dendritic spines. In adulthood, cocaine-induced locomotor activity was exaggerated. By contrast, when administered in adulthood, HA-1077 had no psychomotor consequences and normalized food-reinforced instrumental responding after orbitofrontal-selective knockdown of Brain-derived neurotrophic factor, a potential factor in addiction. Thus, early-life Rho-kinase inhibition confers cocaine vulnerability, but may actually protect against pathological reward-seeking—particularly in cases of diminished neurotrophic support—in adulthood.
The burdens faced by military families who have a child with autism are unique. The usual challenges of securing diagnostic, treatment, and educational services are compounded by life circumstances that include the anxieties of war, frequent relocation and separation, and a demand structure that emphasizes mission readiness and service. Recently established military autism-specific health care benefits set the stage for community-viable and cost-effective solutions that can achieve better outcomes for children and greater well-being for families. Here we argue for implementation of evidence-based solutions focused on reducing age of diagnosis and improving access to early intervention, as well as establishment of a tiered menu of services, individualized to the child and family, that fit with the military ethos and system of health care. Absence of this new model of care could compromise the utility and sustainability of the autism-specific benefit.
by
Alan L. Peterson;
Joseph F. McGuire;
Sabine Wilhelm;
John Piacentini;
Douglas W. Woods;
John T. Walkup;
John P. Hatch;
Robert Villarreal;
Lawrence Scahill
Over the past six decades, behavior therapy has been a major contributor to the development of evidence-based psychotherapy treatments. However, a long-standing concern with behavior therapy among many nonbehavioral clinicians has been the potential risk for symptom substitution. Few studies have been conducted to evaluate symptom substitution in response to behavioral treatments, largely due to measurement and definitional challenges associated with treated psychiatric symptoms. Given the overt motor and vocal tics associated with Tourette's disorder, it presents an excellent opportunity to empirically evaluate the potential risk for symptom substitution associated with behavior therapy. The present study examined the possible presence of symptom substitution using four methods: (a) the onset of new tic symptoms, (b) the occurrence of adverse events, (c) change in tic medications, and (d) worsening of co-occurring psychiatric symptoms. Two hundred twenty-eight participants with Tourette's disorder or persistent motor or vocal tic disorders were randomly assigned to receive behavioral therapy or supportive therapy for tics. Both therapies consisted of eight sessions over 10 weeks. Results indicated that participants treated with behavior therapy were not more likely to have an onset of new tic symptoms, experience adverse events, increase tic medications, or have an exacerbation in co-occurring psychiatric symptoms relative to participants treated with supportive therapy. Further analysis suggested that the emergence of new tics was attributed with the normal waxing and waning nature of Tourette's disorder. Findings provide empirical support to counter the long-standing concern of symptom substitution in response to behavior therapy for individuals with Tourette's disorder.
by
Thilo Deckersbach;
Tina Chou;
Jennifer C. Britton;
Lindsay E. Carlson;
Hannah E. Reese;
Jedidiah Siev;
Lawrence Scahill;
John C. Piacentini;
Douglas W. Woods;
John T. Walkup;
Alan L. Peterson;
Darin D. Dougherty;
Sabine Wilhelm
Tourette's disorder, also called Tourette syndrome (TS), is characterized by motor and vocal tics that can cause significant impairment in daily functioning. Tics are believed to be due to failed inhibition of both associative and motor cortico-striato-thalamo-cortical pathways. Comprehensive Behavioral Intervention for Tics (CBIT), which is an extension of Habit Reversal Therapy (HRT), teaches patients to become more aware of sensations that reliably precede tics (premonitory urges) and to initiate competing movements that inhibit the occurrence of tics. In this study, we used functional magnetic resonance imaging (fMRI) to investigate the neural changes associated with CBIT treatment in subjects with TS. Eight subjects with TS were matched with eight healthy controls in gender, education, age, and handedness. Subjects completed the Visuospatial Priming (VSP) task, a measure of response inhibition, during fMRI scanning before and after CBIT treatment (or waiting period for controls). For TS subjects, we found a significant decrease in striatal (putamen) activation from pre- to post-treatment. Change in VSP task-related activation from pre- to post-treatment in Brodmann's area 47 (the inferior frontal gyrus) was negatively correlated with changes in tic severity. CBIT may promote normalization of aberrant cortico-striato-thalamo-cortical associative and motor pathways in individuals with TS.