Autism spectrum disorder (ASD) is a disorder that is characterized by difficulty in social communication, social skills, and repetitive behavior domains (Sachak, 2016). One of the most prominent features in children with ASD under 3 years of age is delays in language development (Sachak, 2016). This project aims to examine language development in the first year after diagnosis in a sample of preschool children with ASD and to examine family and child demographic characteristics that account for variability in language development. Preschool aged children with ASD (N=59; 7 female) and a matched sample of typically developing (TD) children (N=48; 10 female;) were enrolled in a study of attention and emotion regulation. At enrollment (T1), autism was confirmed using the ADOS module 1 and standardized assessments were done to quantify communication ability (Vineland Adaptive Behavior Scales), nonverbal (visual) reasoning (Mullen Scales of Early Learning), expressive and receptive language (Preschool Language Scale), and self-regulation and executive functioning (Behavior Rating Inventory of Executive Functioning). The PLS, VAB, and BRIEF were repeated at +6 months and +12 months. We hypothesize that: (1) TD children and ASD children who received language interventions will show greater improvement in functional language skills over the first year compared to ASD children ; and (2) children in families with higher household income or education level (one or more parents with college education) will show greater improvements in functional language skills over the 1 year period. Early childhood represents a critical time window for language interventions in order to support functional/adaptive skills and create greater positive outcomes for children with ASD.

Cocaine addiction is a health concern globally. Although both men and women get addicted to cocaine, women transition from casual drug use to addition faster than men, have greater difficulty remaining abstinent and demonstrate greater propensity to relapse. In our laboratory, we found that cocaine craving is potentiated in female rats specifically in the estrus phase of the hormonal cycle. The lateral habenula (LHb), an epithalamic nucleus, plays an important role in cocaine taking and seeking and also mediates several estrogen-dependent behaviors in female rats. In the brain, the effects of estrogen are primarily mediated by estrogen receptors alpha and beta. The goals of this study are - a) to determine if there are hormone-dependent changes in estrogen receptor plasticity in LHb neurons and, b) to define the neuroanatomical organization of estrogen receptors in LHb projection neurons. Firstly, brains from freely-cycling female rats were collected during all phases of the hormonal cycle and analyzed for LHb estrogen receptor expression. Preliminary results indicate that majority of estrogen receptor alpha expressing neurons are located in the ventromedial aspect of the medial to caudal LHb. Analyses are currently underway to determine if cyclical fluctuations in ovarian hormones across the estrus cycle influence estrogen receptor expression in LHb neurons. Secondly, rats were injected with canine adenovirus (CAV2) expressing ZsGreen into either the ventral tegmental area (VTA), dorsal raphe nucleus (DRN) or rostromedial tegmental nucleus (RMTg), three LHb targets. CAV2-ZsGreen vector was retrogradely transported to neuronal cell bodies in the LHb where ZsGreen transgene was expressed. RNAScope in situ hybridization studies are in progress to determine the co-localization of ZsGreen positive neurons in the LHb with estrogen receptors. Understanding the cyclicity of LHb estrogen receptor expression will guide our studies targeted at understanding sex differences in neuronal mechanisms of cocaine taking and seeking behaviors.

Autism Spectrum Disorder (ASD) is characterized by disruptions in social, behavioral, and communication behaviors. Meeting early language milestones has been identified as a strong predictor of positive language outcomes individuals with ASD. Females, compared to males, show better early cognitive and language functioning, including high risk infants with and without ASD outcomes. Less is known about language trajectories in females with ASD, as they often make up a minority of research participants. In this study, we want to evaluate the relationship between early language milestones and youth language and communication ability in a sex balanced sample with ASD. The project included 137 youths, 60 females and 77 males, from ages 8-18 years with ASD. To assess language, parents reported from the ACE Medical History, which reports on age at first words and age at 3-word phrases which were confirmed with similar items in the ADI. The participant completed the CELF-4, with analysis focusing on the subdomains Recalling Sentences and Formulating Sentences, and the parent completed the Vineland Adaptive Behavior (Communication Domain). Our preliminary analysis demonstrated significant differences by sex in early language milestones as well as relation to later better language ability as a youth. Age at first words was related to later language, but only in females with ASD; while age at 3 words was related to later outcomes for males and females. It is important to understand how language develops different in males and females with ASD and being able to recognize risk factors at a young age for more accurate intervention.

Fear is an emotion that is triggered when an organism encounters danger or threat. Once fear is triggered, the nervous system induces many physical changes, and the brain responds accordingly to elicit defensive or fleeing behavior. Such fear responses are known to involve a critical brain region called the amygdala. One of the ways in which the amygdala mediates fear response is by secreting a neuropeptide called corticotropin-releasing factor (CRF). Our lab has previously found that CRF-expressing neurons in the central nucleus of the amygdala (CeA-CRF neurons) facilitate the acquisition of discriminatory fear responses and prevent fear extinction. In contrast, others have reported that activation of CeA-CRF neurons is reinforcing. To resolve these contradictory findings, we investigated the functional roles of CeA-CRF neurons in naïve and fear-conditioned mice. We hypothesized that activation of CeA-CRF neurons in a neutral context may produce reinforcing effects by signaling a type of salience. However, following a fearful experience these neurons may signal the aversive nature of this experience. To stimulate CeA-CRF neurons selectively, we used optogenetics, in which light-sensitive ion channel-expressing neurons are stimulated using light, and animals underwent several behavioral tasks including operant conditioning for lever pressing, real time place preference task, and elevated plus maze test. Based on the animals’ emotional context (naïve or fear-conditioned), we examined how stimulation of CeA-CRF neurons affected the animals’ behavioral performances. Our results showed that stimulating CeA-CRF in naïve mice produced no effects. However, if the animal’s first experience in a context was appetitive, then stimulating in this context is reinforcing. Similarly, if an animal’s experience is aversive, then stimulating these neurons perpetuates fear and anxiety behaviors. These results suggest that CeA-CRF neurons signal context-dependent behavioral state effects that may be important for engaging appropriate actions in specific contexts.

The hippocampus (HPC) and lateral habenula (LHb) work together to guide flexible responding as one’s environment changes. The HPC plays a critical role in learning and remembering events. While the LHb has been shown to encode information about rewards and aversive events, it also enables flexible responding during HPC-dependent tasks. Therefore, we hypothesized that the LHb and HPC communicate during choices, as this should be when the two structures combine reward information and spatial memory to make a decision. It is generally thought that brain structures are communicating when their neural oscillatory activity is coupled. Thus, we measured the activity of large populations of cells in the LHb and HPC while rats performed a spatial memory task. We expected to see higher coherence of oscillatory activity during choices than during other phases of the task, as this would suggest the HPC and LHb are interacting to process reward information and spatial memory in a flexible manner. However, our preliminary results showed that the population activity recorded in the LHb is likely inherited from the HPC by volume conduction, which means that the LHb oscillation is not locally generated. A future direction is to improve our recording method and investigate single-cell characteristics in the LHb with respect to hippocampal oscillations. Overall, this work is important because it guides future steps for studying the communication between the LHb and HPC, which could provide insights on pathological conditions where a person is unable to flexibly respond in a changing context (such as in depression, addiction, or memory disorders). Therefore, future findings from our research may have important clinical applications, with the potential to inform and improve upon existing interventions for disorders of memory and mood.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that is commonly associated with deficits in social, adaptive, and communication skills. Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by inattention, hyperactivity, and impulsivity that impairs functioning. Previous research estimates that between 30 and 50% of individuals with ASD manifest ADHD symptoms. Although research has shown that individuals with ASD tend to have decreased community involvement, it is not well studied in individuals who have co-occurring ASD and ADHD. The current study explores the relationship between social or community engagement (involvement in organizations, sports, organized group activities) and adaptive skills of individuals with ASD or ASD+ADHD. Participants included 110 youth (m=66, f=44), 8-17 years of age with ASD from the ACE GENDAAR network, a four-site NIH funded project examining sex-based neural differences in children with ASD. All participants included in the sample met ASD criteria on standardized autism assessments (ADOS-2 and ADI-R) and scored ≥70 on a measure of verbal IQ (DAS-II). Parents completed the Child Behavior Checklist (CBCL) reporting on child activity (involvement in sports, organizations, hobbies, chores), ADHD symptoms, overall behavioral problems, and overall competence. Parents also completed the Vineland-II, a parent interview assessing adaptive skills. We hypothesize that there will be a positive correlation between social activity involvement and adaptive skills. That is, children with more community participation will have better adaptive ability. Furthermore, we expect that children with ASD+ADHD compared to children with ASD only, will have greater impairment in adaptive skills and will score lower on the activities scale. The results of this study will provide further understanding of ASD+ADHD and barriers to children participating in community activities and organizations.

Many neuropsychiatric disorders such as schizophrenia and major depression are linked to deficits in memory and decision making. The hippocampus (HPC) and medial prefrontal cortex (mPFC) are two brain structures that communicate during these cognitive operations through synchrony at the theta rhythm (4-12hz). Understanding faulty communication between HPC and mPFC may bring us closer to developing treatments to help individuals suffering from these neuropsychiatric disorders. The focus of this research was to uncover whether disrupting HPC-mPFC communication at specific phases of the theta cycle (peak/trough) would reveal distinct spatial working memory impairments. We employed a novel closed-loop system that allowed us to record and detect the peak and troughs of the HPC theta rhythm of rats performing on a spatial working memory task that is known to be HPC and mPFC dependent. Upon theta phase detection, the mPFC was stimulated to disrupt the flow of information being sent between these two structures. Disrupting this communication at specific phases of the theta cycle may affect different memory processes such as encoding and retrieval. Thus we varied disruption along 3 different task epochs in which different mnemonic functions are thought to occur. Initial findings revealed no significant theta-phase effect. However, there was a significant accuracy deficit when HPC-mPFC communication was disrupted during the choice epoch compared to other epochs. Our findings suggest that there is something unique about HPC-mPFC interactions at the choice point that is necessary for accurate spatial working memory. Our findings support the view that miscommunications between the HPC and mPFC leads to poorer memory function. Future research can determine if neuropsychiatric patients suffer from impaired communication between the HPC and mPFC.

The midbrain dopamine system consists of neurons in the ventral tegmental area, which release dopamine to other parts of the brain. This system is associated with how the brain processes reward, associative learning, and executive action. Dopamine neurons maintain basal levels of dopamine through slow, single spike tonic firing patterns; when a stimulus is presented these neurons transition into tightly regulated, transient phasic activity patterns. Disruptions to this tonic-phasic balance in the dopamine system have been linked to neurological and neuropsychiatric disorders like Parkinson’s disorder, major depressive disorder and substance-use disorder. We used viral based and cell specific CRISPR/Cas9 gene mutagenesis to target the genes of two voltage gated ion channels in adult DATiCre Mice: Kcnd3 (the gene for Kv4.3 ion channel subunits) and Kcnma1 (the gene for BKCa1.1 ion channel subunits). We discovered that loss of Kv4.3 ion channel subunit function increased tonic firing patterns, while loss of the BKCa1.1 ion channel subunit increased phasic patterns. We ran behavioral assays to assess the associative learning ability of these mice. Based on our physiological findings, we hypothesize that Kcnd3 and Kcnma1 treatment groups would exhibit slower learning of reward-associated behaviors. Understanding how the tonic-phasic balance works to maintain healthy behavioral function in mice would be a big step in dealing with the neurological and neuropsychiatric disorders that plague our society.