Increased Dendrite Branching in AβPP/PS1 Mice and Elongation of Dendrite Arbors by Fasudil Administration

Amyloid-β (Aβ) overproduction and dendrite arbor atrophy are hallmarks of Alzheimer’s disease. The RhoA GTPase (Rho) signals through Rho kinase (ROCK) to control cytoskeletal dynamics and regulate neuron structure. Hyperactive Rho signaling destabilizes neurons leading to dendritic regression that can be rescued by genetic or pharmacological reduction of ROCK signaling. To understand what effect reduced ROCK signaling has on the dendrite arbors of mice that overproduce Aβ, we administered the ROCK inhibitor fasudil to AβPP/PS1 transgenic mice. We report that increased dendrite branching occurs in AβPP/PS1 mice and that fasudil promotes lengthening of the dendrite arbors of CA1 pyramidal neurons

Selective Role of the Catalytic PI3K Subunit p110β in Impaired Higher Order Cognition in Fragile X Syndrome

SummaryDistinct isoforms of the PI3K catalytic subunit have specialized functions in the brain, but their role in cognition is unknown. Here, we show that the catalytic subunit p110β plays an important role in prefrontal cortex (PFC)-dependent cognitive defects in mouse models of Fragile X syndrome (FXS), an inherited intellectual disability. FXS is caused by loss of function of the fragile X mental retardation protein (FMRP), which binds and translationally represses mRNAs. PFC-selective knockdown of p110β, an FMRP target that is translationally upregulated in FXS, reverses deficits in higher cognition in Fmr1 knockout mice. Genetic full-body reduction of p110β in Fmr1 knockout mice normalizes excessive PI3K activity, restores stimulus-induced protein synthesis, and corrects increased dendritic spine density and behavior. Notably, adult-onset PFC-selective Fmr1 knockdown mice show impaired cognition, which is rescued by simultaneous p110β knockdown. Our results suggest that FMRP-mediated control of p110β is crucial for neuronal protein synthesis and cognition

Adolescent Corticosterone and TrkB Pharmaco-Manipulations Sex-Dependently Impact Instrumental Reversal Learning Later in Life

Early-life trauma can increase the risk for, and severity of, several psychiatric illnesses. These include drug use disorders, and some correlations appear to be stronger in women. Understanding the long-term consequences of developmental stressor or stress hormone exposure and possible sex differences is critically important. So-called “reversal learning” tasks are commonly used in rodents to model cognitive deficits in stress- and addiction-related illnesses in humans. Here, we exposed mice to the primary stress hormone corticosterone (CORT) during early adolescence (postnatal days 31–42), then tested behavioral flexibility in adulthood using an instrumental reversal learning task. CORT-exposed female, but not male, mice developed perseverative errors. Despite resilience to subchronic CORT exposure, males developed reversal performance impairments following exposure to physical stressors. Administration of a putative tyrosine kinase receptor B (trkB) agonist, 7,8-dihydroxyflavone (7,8-DHF), during adolescence blocked CORT-induced errors in females and improved performance in males. Conversely, blockade of trkB by ANA-12 impaired performance. These data suggest that trkB-based interventions could have certain protective benefits in the context of early-life stressor exposure. We consider the implications of our findings in an extended “Discussion” section

Pyk2 Stabilizes Striatal Medium Spiny Neuron Structure and Striatal-Dependent Action

In day-to-day life, we often choose between pursuing familiar behaviors that have been rewarded in the past or adjusting behaviors when new strategies might be more fruitful. The dorsomedial striatum (DMS) is indispensable for flexibly arbitrating between old and new behavioral strategies. The way in which DMS neurons host stable connections necessary for sustained flexibility is still being defined. An entry point to addressing this question may be the structural scaffolds on DMS neurons that house synaptic connections. We find that the non-receptor tyrosine kinase Proline-rich tyrosine kinase 2 (Pyk2) stabilizes both dendrites and spines on striatal medium spiny neurons, such that Pyk2 loss causes dendrite arbor and spine loss. Viral-mediated Pyk2 silencing in the DMS obstructs the ability of mice to arbitrate between rewarded and non-rewarded behaviors. Meanwhile, the overexpression of Pyk2 or the closely related focal adhesion kinase (FAK) enhances this ability. Finally, experiments using combinatorial viral vector strategies suggest that flexible, Pyk2-dependent action involves inputs from the medial prefrontal cortex (mPFC), but not the ventrolateral orbitofrontal cortex (OFC). Thus, Pyk2 stabilizes the striatal medium spiny neuron structure, likely providing substrates for inputs, and supports the capacity of mice to arbitrate between novel and familiar behaviors, including via interactions with the medial-prefrontal cortex

Arbitration between Actions and Habits: Cortical Regulators and the Influence of Cocaine

Presented on January 29, 2018 at 11:15 a.m. in the Krone Engineered Biosystems Building, Room 1005.Shannon Gourley is an Assistant Professor in the Department of Pediatrics and Psychiatry at Emory University. Her research team aims to understand why adolescence is a period of vulnerability to the development of multiple psychiatric illnesses.Runtime: 54:27 minutesSelecting actions based on their consequences is essential to day-to-day function and yet, is impaired in neuropsychiatric diseases like addiction. Goal-directed action selection likely requires the coordinated output of multiple prefrontal cortical structures, but mechanistic factors are still being identified. I will focus on the neurotrophin BDNF in the orbital prefrontal cortex and PI3-kinase in the medial prefrontal cortex, providing evidence that they are key molecular mechanisms by which the brain coordinates goal-directed action. These findings serve as a platform from which to improve goal-directed action selection following developmental cocaine

Increased Dendrite Branching in AβPP/PS1 Mice and Elongation of Dendrite Arbors by Fasudil Administration

Amyloid-β (Aβ) overproduction and dendrite arbor atrophy are hallmarks of Alzheimer’s disease. The RhoA GTPase (Rho) signals through Rho kinase (ROCK) to control cytoskeletal dynamics and regulate neuron structure. Hyperactive Rho signaling destabilizes neurons leading to dendritic regression that can be rescued by genetic or pharmacological reduction of ROCK signaling. To understand what effect reduced ROCK signaling has on the dendrite arbors of mice that overproduce Aβ, we administered the ROCK inhibitor fasudil to AβPP/PS1 transgenic mice. We report that increased dendrite branching occurs in AβPP/PS1 mice and that fasudil promotes lengthening of the dendrite arbors of CA1 pyramidal neurons

Long-Term Consequences of Adolescent Drug Use: Evidence from Pre-Clinical and Clinical Models

The purpose of this collection is to provide a forum to integrate pre-clinical and clinical investigations regarding the long-term consequences of adolescent exposure to drugs of abuse. Adolescence is characterized by numerous behavioral and biological changes, including substantial neurodevelopment. Behaviorally, adolescents are more likely to engage in risky activities and make impulsive decisions. As such, the majority of substance use begins in adolescence, and an earlier age of onset of use (<15 yr) is strongly associated with the risk for developing a substance use disorder later in life. Furthermore, adolescent drug use may negatively impact ongoing neurological development, which could lead to long-term cognitive and emotional deficits. A large number of clinical studies have investigated both the acute and long-term effects of adolescent drug use on functional outcomes. However, the clinical literature contains many conflicting findings, and is often hampered by the inability to know if functional differences existed prior to drug use. Moreover, in human populations it is often very difficult to control for the numerous types of drugs, doses, and combinations used, not to mention the many other environmental factors that may influence adult behavior. Therefore, an increase in the number of carefully controlled studies using relevant animal models has the potential to clarify which adolescent experiences, particularly what drugs used when, have long-term negative consequences. Despite the advantages of animal model systems in clarifying these issues, the majority of pre-clinical addiction research over the past 50+ years has been conducted in adult animals. Moreover, few addiction-related studies have investigated the long-term neurocognitive consequences of drug exposure at any age. In the past 10 years of so, however, the field of adolescent drug abuse research has burgeoned. To date, the majority of this research has focused on adolescent alcohol exposure using a variety of animal models. The results have given the field important insight into why adolescents are more likely to drink alcohol to excess relative to adults, and the danger of adolescent alcohol use (e.g., in leading to a persistence of excessive drinking in adulthood). More recently, research regarding the effects of adolescent exposure to other drugs of abuse, including nicotine, cocaine, and cannabinoids has expanded. Therefore, we are at unique point in time, when emerging results from carefully controlled pre-clinical studies can inform the sometimes confusing clinical literature. In addition, we expect an influx of prospective clinical studies in response to a cross-institute initiative at NIH, known as the ABCD grant. Several institutes are enrolling children prior to adolescence (and the initiation of drug use), in order to control for pre-existing neurobiological and neurobehavioral differences and to monitor the age of initiation and amount of drug used more carefully than is possible using retrospective designs