Since its founding in 2017, the CCB has financially supported a variety of research investigations. While some of these projects are only just beginning, others, listed below, have been submitted to and published by neuroscience academic journals. Please note that future papers will be added to this list as they are published.
A Note for CCB Fellows
If research you completed with the help of CCB funding is in the process of being submitted for publication, please include the following affiliation and acknowledgement statements in your paper:
Affiliation:
Center on Compulsive Behaviors, Intramural Research Program, NIH, Bethesda, MD, USA
Funding:
This study was funded by the Center on Compulsive Behaviors, NIH via the NIH Shared Resource Subcommittee to (YOUR INITIALS HERE)
2024 |
Talluri, Bharath Chandra; Nienborg, Hendrikje Tracking the evolution of a single choice Journal Article In: Elife, vol. 13, 2024, ISSN: 2050-084X. @article{pmid39429097,Measuring the activity of hundreds of neurons in macaque brains simultaneously provides further evidence that drift-diffusion dynamics underlie how decisions are made in the brain. |
Goral, Rene Oliver; Lamb, Patricia W; Yakel, Jerrel L Acetylcholine Neurons Become Cholinergic during Three Time Windows in the Developing Mouse Brain Journal Article In: eNeuro, vol. 11, no. 7, 2024, ISSN: 2373-2822. @article{pmid38942474,Acetylcholine (ACh) neurons in the central nervous system are required for the coordination of neural network activity during higher brain functions, such as attention, learning, and memory, as well as locomotion. Disturbed cholinergic signaling has been described in many neurodevelopmental and neurodegenerative disorders. Furthermore, cotransmission of other signaling molecules, such as glutamate and GABA, with ACh has been associated with essential roles in brain function or disease. However, it is unknown when ACh neurons become cholinergic during development. Thus, understanding the timeline of how the cholinergic system develops and becomes active in the healthy brain is a crucial part of understanding brain development. To study this, we used transgenic mice to selectively label ACh neurons with tdTomato. We imaged serial sectioned brains and generated whole-brain reconstructions at different time points during pre- and postnatal development. We found three crucial time windows-two in the prenatal and one in the postnatal brain-during which most ACh neuron populations become cholinergic in the brain. We also found that cholinergic gene expression is initiated in cortical ACh interneurons, while the cerebral cortex is innervated by cholinergic projection neurons from the basal forebrain. Taken together, we show that ACh neuron populations are present and become cholinergic before postnatal day 12, which is the onset of major sensory processes, such as hearing and vision. We conclude that the birth of ACh neurons and initiation of cholinergic gene expression are temporally separated during development but highly coordinated by brain anatomical structure. |
Gunawan, Tommy; Luk, Jeremy W; Schwandt, Melanie L; Kwako, Laura E; Vinson, Tonette; Horneffer, Yvonne; George, David T; Koob, George F; Ramchandani, Vijay A; Diazgranados, Nancy; Goldman, David Factors underlying the neurofunctional domains of the Addictions Neuroclinical Assessment assessed by a standardized neurocognitive battery Journal Article In: Transl Psychiatry, vol. 14, no. 1, pp. 271, 2024, ISSN: 2158-3188. @article{pmid38956031,The Addictions Neuroclinical Assessment (ANA) is a neurobiologically-informed framework designed to understand the etiology and heterogeneity of Alcohol Use Disorder (AUD). Previous studies validated the three neurofunctional domains of ANA: Incentive Salience (IS), Negative Emotionality (NE) and Executive Function (EF) using secondary data. The present cross-sectional observational study assessed these domains in an independent, prospective clinical sample. Adults across the drinking spectrum (N = 300) completed the ANA battery, a standardized collection of behavioral tasks and self-report assessments. Factor analyses were used to identify latent factors underlying each domain. Associations between identified domain factors were evaluated using structural equation models. Receiver operating characteristics analyses were used to determine factors with the strongest ability to classify individuals with problematic drinking and AUD. We found (1) two factors underlie the IS domain: alcohol motivation and alcohol insensitivity. (2) Three factors were identified for the NE domain: internalizing, externalizing, and psychological strength. (3) Five factors were found for the EF domain: inhibitory control, working memory, rumination, interoception, and impulsivity. (4) These ten factors showed varying degrees of cross-correlations, with alcohol motivation, internalizing, and impulsivity exhibiting the strongest correlations. (5) Alcohol motivation, alcohol insensitivity, and impulsivity showed the greatest ability in classifying individuals with problematic drinking and AUD. Thus, the present study identified unique factors underlying each ANA domain assessed using a standardized assessment battery. These results revealed additional dimensionality to the ANA domains, bringing together different constructs from the field into a single cohesive framework and advancing the field of addiction phenotyping. Future work will focus on identifying neurobiological correlates and identifying AUD subtypes based on these factors. |
Liu, Qingfang; Zhao, Yao; Attanti, Sumedha; Voss, Joel L; Schoenbaum, Geoffrey; Kahnt, Thorsten Midbrain signaling of identity prediction errors depends on orbitofrontal cortex networks Journal Article In: Nat Commun, vol. 15, no. 1, pp. 1704, 2024, ISSN: 2041-1723. @article{pmid38402210b,Outcome-guided behavior requires knowledge about the identity of future rewards. Previous work across species has shown that the dopaminergic midbrain responds to violations in expected reward identity and that the lateral orbitofrontal cortex (OFC) represents reward identity expectations. Here we used network-targeted transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) during a trans-reinforcer reversal learning task to test the hypothesis that outcome expectations in the lateral OFC contribute to the computation of identity prediction errors (iPE) in the midbrain. Network-targeted TMS aiming at lateral OFC reduced the global connectedness of the lateral OFC and impaired reward identity learning in the first block of trials. Critically, TMS disrupted neural representations of expected reward identity in the OFC and modulated iPE responses in the midbrain. These results support the idea that iPE signals in the dopaminergic midbrain are computed based on outcome expectations represented in the lateral OFC. |
Tyler, Ryan E; Leggio, Lorenzo Biological basis of addiction and alcohol use disorder Journal Article In: Clin Liver Dis (Hoboken), vol. 23, no. 1, pp. e0177, 2024, ISSN: 2046-2484. @article{pmid38831763, |
Agarwal, Khushbu; Luk, Jeremy W; Stangl, Bethany L; Schwandt, Melanie L; Momenan, Reza; Goldman, David; Diazgranados, Nancy; Kareken, David A; Leggio, Lorenzo; Ramchandani, Vijay A; Joseph, Paule V Parosmia Is Positively Associated With Problematic Drinking, as Is Phantosmia With Depressive Symptoms Journal Article In: J Addict Med, vol. 18, no. 5, pp. 567–573, 2024, ISSN: 1935-3227. @article{pmid38776446,OBJECTIVES: Alcohol use disorder (AUD) is a global health problem with significant negative consequences, including preventable deaths. Although olfactory dysfunction is associated with chronic alcohol drinking, the relationship among specific types of olfactory deficits, depressive symptoms, and problematic drinking remains to be explored. Here, we examined the prevalence of olfactory distortion (parosmia) and hallucination (phantosmia) and assessed their associations with problematic drinking and depressive symptoms.nnMETHODS: In April-June 2022, 250 participants across the spectrum of AUD were recruited for assessment in the National Institute on Alcohol Abuse and Alcoholism COVID-19 Pandemic Impact on Alcohol study. Surveys covered self-reported olfactory function, depressive symptoms, and problematic drinking, with key measures assessed, including the Alcohol Use Disorders Identification Test and the Patient Health Questionnaire. Predictors in the analysis included parosmia and phantosmia, with covariates comprising age, sex, socioeconomic status, race, ethnicity, COVID-19 infection status, and smoking status.nnRESULTS: Among 250 individuals, 5.2% experienced parosmia and 4.4% reported phantosmia. Parosmia was associated with higher Alcohol Use Disorders Identification Test scores (β = 7.14; 95% confidence interval = 3.31, 10.96; P < 0.001), whereas phantosmia was linked to higher Patient Health Questionnaire scores (β = 3.32; 95% confidence interval = 0.22, 6.42; P = 0.03). These associations persisted in both the full sample and the subset of participants without COVID-19.nnCONCLUSIONS: Our study highlights strong existing links among olfactory deficits, problem drinking, and depressive symptoms, underscoring the need to assess smell impairments in clinical settings. Future research should explore these connections further to develop new treatments for individuals with AUD and depression. |
2023 |
Letsinger, Ayland C; Ward, James M; Fannin, Rick D; Mahapatra, Debabrata; Bridge, Matthew F; Sills, Robert C; Gerrish, Kevin E; Yakel, Jerrel L Nicotine exposure decreases likelihood of SARS-CoV-2 RNA expression and neuropathology in the hACE2 mouse brain but not moribundity Journal Article In: Sci Rep, vol. 13, no. 1, pp. 2042, 2023, ISSN: 2045-2322. @article{pmid36739463,Individuals infected by SARS-CoV-2 are at risk of developing neurological-related post-acute disorders. Disputed epidemiological data indicated nicotine may reduce the severity of infection. Here we find exposure to nicotine in drinking water does not alter the moribundity of hACE2 mice. However, pre-exposure to nicotine decreased the likelihood of SARS-CoV-2 RNA expression and pathology in the brain. These results suggest mechanisms involving targets of nicotine could be leveraged to prevent the neurovirulence of SARS-CoV-2. |
Burk, Diana C; Averbeck, Bruno B Environmental uncertainty and the advantage of impulsive choice strategies Journal Article In: PLoS Comput Biol, vol. 19, no. 1, pp. e1010873, 2023, ISSN: 1553-7358. @article{pmid36716320,Choice impulsivity is characterized by the choice of immediate, smaller reward options over future, larger reward options, and is often thought to be associated with negative life outcomes. However, some environments make future rewards more uncertain, and in these environments impulsive choices can be beneficial. Here we examined the conditions under which impulsive vs. non-impulsive decision strategies would be advantageous. We used Markov Decision Processes (MDPs) to model three common decision-making tasks: Temporal Discounting, Information Sampling, and an Explore-Exploit task. We manipulated environmental variables to create circumstances where future outcomes were relatively uncertain. We then manipulated the discount factor of an MDP agent, which affects the value of immediate versus future rewards, to model impulsive and non-impulsive behavior. This allowed us to examine the performance of impulsive and non-impulsive agents in more or less predictable environments. In Temporal Discounting, we manipulated the transition probability to delayed rewards and found that the agent with the lower discount factor (i.e. the impulsive agent) collected more average reward than the agent with a higher discount factor (the non-impulsive agent) by selecting immediate reward options when the probability of receiving the future reward was low. In the Information Sampling task, we manipulated the amount of information obtained with each sample. When sampling led to small information gains, the impulsive MDP agent collected more average reward than the non-impulsive agent. Third, in the Explore-Exploit task, we manipulated the substitution rate for novel options. When the substitution rate was high, the impulsive agent again performed better than the non-impulsive agent, as it explored the novel options less and instead exploited options with known reward values. The results of these analyses show that impulsivity can be advantageous in environments that are unexpectedly uncertain. |
Nguyen, Thien; Park, Soongho; Hill, Brian; Gandjbakhche, Amir H. Single Source-Detector Separation Approach to Calculate Tissue Oxygen Saturation Using Continuous Wave Near-Infrared Spectroscopy Journal Article In: IEEE Open Journal of Engineering in Medicine and Biology, vol. 4, pp. 79-84, 2023, ISSN: 2644-1276. @article{10049463,Currently, common optical techniques to measure tissue oxygen saturation (StO2) include time domain (TD), frequency domain (FD), and continuous wave (CW) near-infrared spectroscopy (NIRS). While TD- and FD-NIRS can provide absolute hemoglobin concentration, these systems are often complex and expensive. CW-NIRS, such as diffuse reflectance spectroscopy and spatially resolved spectroscopy (SRS), are simpler and more affordable, but they still require at least two source-detector separations. Here, we propose a single source-detector separation (SSDS) approach to measure StO2 using reflected intensities from three wavelengths. The accuracy of the SSDS-based StO2 measurement was verified using an optical simulation and an in-vivo experiment. Simulated spatially dependent reflectance was generated using the Virtual Tissue Simulator on a 1-layer model, which has StO2 ranging from 0% to 100%. SSDS calculation yielded an equivalent StO2 to the actual value (average error = 0.3% ± 0.5%). We then performed StO2 measurements on seven healthy volunteers in the prefrontal cortex during a simulated hypercapnia test using a CW-NIRS device. This device consists of a light source and two photodetectors, which are 30 mm and 40 mm away from the light source. The cerebral oxygen saturation was calculated using both the SRS approach, which uses the reflected intensities at both separations, and the SSDS approach, which employs the reflected intensities at either 30 mm or 40 mm separation. The SRS-based StO2 calculation was similar to the value calculated from the SSDS method (average difference = 5.0% ± 1.1%). This proposed method will help to advance the development of miniaturized technologies to monitor StO2 continuously. |
Agarwal, Khushbu; Luk, Jeremy W; Manza, Peter; McDuffie, Christian; To, Leann; Jaime-Lara, Rosario B; Stangl, Bethany L; Schwandt, Melanie L; Momenan, Reza; Goldman, David; Diazgranados, Nancy; Ramchandani, Vijay A; Joseph, Paule V Chemosensory Alterations and Impact on Quality of Life in Persistent Alcohol Drinkers Journal Article In: Alcohol Alcohol, vol. 58, no. 1, pp. 84–92, 2023, ISSN: 1464-3502. @article{pmid36208183,BACKGROUND: Heavy alcohol consumption-associated chemosensory dysfunction is understudied, and early detection can help predict disease-associated comorbidities, especially those related to four quality of life (QOL) domains (physical, psychological, social and environment). We examined self-reports of chemosensory ability of individuals with different alcohol drinking behaviors and their association with changes in QOL domains.nnMETHODS: Participants (n = 466) were recruited between June 2020 and September 2021 into the NIAAA COVID-19 Pandemic Impact on Alcohol study. Group-based trajectory modeling was used to categorize participants without any known COVID-19 infection into three groups (non-drinkers, moderate drinkers and heavy drinkers) based on their Alcohol Use Disorders Identification Test consumption scores at four different time points (at enrollment, week 4, week 8 and week 12). Linear mixed models were used to examine chemosensory differences between these groups. The associations between chemosensory abilities and QOL were determined in each group.nnRESULTS: We observed significant impairment in self-reported smell ability of heavy drinking individuals compared to non-drinkers. In contrast, taste ability showed marginal impairment between these groups. There were no significant differences in smell and taste abilities between the moderate and non-drinking groups. Heavy drinkers' impairment in smell and taste abilities was significantly associated with deterioration in their physical, psychological, social and environmental QOL.nnCONCLUSION: Persistent heavy drinking was associated with lower chemosensory ability. Heavy drinkers' reduced smell and taste function and association with poorer QOL indicate that early assessment of chemosensory changes may be crucial in identifying poorer well-being outcomes in heavy drinkers at risk for alcohol use disorder. |
2022 |
Beacher, Nicholas James; Washington, Kayden Alecsandre; Zhang, Yan; Li, Yun; Lin, Da-Ting GRIN lens applications for studying neurobiology of substance use disorder Journal Article In: Addict Neurosci, vol. 4, 2022, ISSN: 2772-3925. @article{pmid36531187,Substance use disorder (SUD) is associated with severe health and social consequences. Continued drug use results in alterations of circuits within the mesolimbic dopamine system. It is critical to observe longitudinal impacts of SUD on neural activity to identify SUD predispositions, develop pharmaceuticals to prevent overdose, and help people suffering from SUD. However, implicated SUD associated areas are buried in deep brain which makes observation of neural activity challenging. The gradient index (GRIN) lens can probe these regions in mice and rats. In this short communications review, we will discuss how the GRIN lens can be coupled with other technologies such as miniaturized microscopes, fiberscopes, fMRI, and optogenetics to fully explore SUD research. Particularly, GRIN lens allows observation of deep brain regions implicated in SUD, differentiation of genetically distinct neurons, examination of individual cells longitudinally, correlation of neuronal patters with SUD behavior, and manipulation of neural circuits. |
Agarwal, Khushbu; Manza, Peter; Tejeda, Hugo A; Courville, Amber B; Volkow, Nora D; Joseph, Paule V In: Nutrients, vol. 14, no. 21, 2022, ISSN: 2072-6643. @article{pmid36364905,Prenatal caffeine exposure (PCE) has been positively associated with elevated body mass index (BMI) in children. Why this association occurs is unclear, but it is possible that PCE alters the in utero development of brain structures associated with food preference, leading to more total sugar intake (TSI, grams) later in childhood. To test this hypothesis, we investigated if PCE (daily/weekly/<weekly vs. no exposure) and elevated BMI are associated with increased TSI, neural activation during large reward anticipation (monetary incentive delay task—functional MRI) and structural changes (thickness, mm) in taste processing regions of children (n = 5534; 9−11 years) from the large-scale Adolescent Brain Cognitive Development (ABCD) study. Linear mixed-effect models, after covariate adjustments, identified a positive association (p < 0.05, all |βs| > 0.01) of excessive PCE (vs. no exposure) with elevated BMI (daily/weekly/daily limit; consistent in boys and girls), increased TSI (daily) and insular thickness (daily/weekly), as well as low middle frontal cortex (MFC) activation (daily). Our sub-analysis revealed an association of daily/weekly PCE (vs. no exposure) with increased gram sugar intake from soft drinks. We also identified a positive relationship of excessive PCE with elevated TSI and increased insular thickness (a key gustatory region), while in a Sobel test, reward sensitivity (reduced brain reactivity to reward anticipation in MFC; tracks reward outcomes) mediated (Test statistic = 2.23; p = 0.02) the PCE-linked BMI changes in adolescents. Our findings suggest that excessive PCE might be detrimental to frontal lobe development and altered reward sensitivity to food, thereby increasing risk for elevated TSI and obesity. Our results support recommendations to limit caffeine intake during pregnancy. |
Singh, Sudhuman; Wilson, Torri D; Valdivia, Spring; Benowitz, Barbara; Chaudhry, Sarah; Ma, Jun; Adke, Anisha P; Soler-Cedeño, Omar; Velasquez, Daniela; Penzo, Mario A; Carrasquillo, Yarimar An inhibitory circuit from central amygdala to zona incerta drives pain-related behaviors in mice Journal Article In: Elife, vol. 11, 2022, ISSN: 2050-084X. @article{pmid36269044,Central amygdala neurons expressing protein kinase C-delta (CeA-PKCδ) are sensitized following nerve injury and promote pain-related responses in mice. The neural circuits underlying modulation of pain-related behaviors by CeA-PKCδ neurons, however, remain unknown. In this study, we identified a neural circuit that originates in CeA-PKCδ neurons and terminates in the ventral region of the zona incerta (ZI), a subthalamic structure previously linked to pain processing. Behavioral experiments show that chemogenetic inhibition of GABAergic ZI neurons induced bilateral hypersensitivity in uninjured mice and contralateral hypersensitivity after nerve injury. In contrast, chemogenetic activation of GABAergic ZI neurons reversed nerve injury-induced hypersensitivity. Optogenetic manipulations of CeA-PKCδ axonal terminals in the ZI further showed that inhibition of this pathway reduces nerve injury-induced hypersensitivity whereas activation of the pathway produces hypersensitivity in the uninjured paws. Altogether, our results identify a novel nociceptive inhibitory efferent pathway from CeA-PKCδ neurons to the ZI that bidirectionally modulates pain-related behaviors in mice. |
Kesner, Andrew J; Calva, Coleman B; Ikemoto, Satoshi Seeking motivation and reward: Roles of dopamine, hippocampus, and supramammillo-septal pathway Journal Article In: Prog Neurobiol, vol. 212, pp. 102252, 2022, ISSN: 1873-5118. @article{pmid35227866b,Reinforcement learning and goal-seeking behavior are thought to be mediated by midbrain dopamine neurons. However, little is known about neural substrates of curiosity and exploratory behavior, which occur in the absence of clear goal or reward. This is despite behavioral scientists having long suggested that curiosity and exploratory behaviors are regulated by an innate drive. We refer to such behavior as information-seeking behavior and propose 1) key neural substrates and 2) the concept of environment prediction error as a framework to understand information-seeking processes. The cognitive aspect of information-seeking behavior, including the perception of salience and uncertainty, involves, in part, the pathways from the posterior hypothalamic supramammillary region to the hippocampal formation. The vigor of such behavior is modulated by the following: supramammillary glutamatergic neurons; their projections to medial septal glutamatergic neurons; and the projections of medial septal glutamatergic neurons to ventral tegmental dopaminergic neurons. Phasic responses of dopaminergic neurons are characterized as signaling potentially important stimuli rather than rewards. This paper describes how novel stimuli and uncertainty trigger seeking motivation and how these neural substrates modulate information-seeking behavior. |
2021 |
Condy, Emma; Kaat, Aaron J; Becker, Lindsey; Sullivan, Nancy; Soorya, Latha; Berger, Natalie; Berry-Kravis, Elizabeth; Michalak, Claire; Thurm, Audrey A novel measure of matching categories for early development: Item creation and pilot feasibility study Journal Article In: Res Dev Disabil, vol. 115, pp. 103993, 2021, ISSN: 1873-3379. @article{pmid34049209,BACKGROUND: Many cognitive tests assess a limited developmental span, making longitudinal measurement for trials aimed at improving cognition challenging. Tests targeting transitional skills, which integrate foundational abilities into complex schemas, may be amenable to assessment across a wide developmental span. Furthermore, tablet-based tests permit computer adaptive testing (CAT), which is psychometrically more efficient and could increase testing motivation, especially for children with developmental delays. Such measures may be useful for research and clinical practice.nnAIMS: Outline the creation of a novel, tablet-based concept formation test, and evaluate its feasibility in individuals with mental ages less than 24-months.nnMETHODS AND PROCEDURES: Item generation, user interface construction, and pre-piloting were conducted in consultation with subject matter experts. Item content and interface parameters underwent iterative revisions, resulting in the pilot test.nnOUTCOMES AND RESULTS: We created and piloted a tablet-based test of concept formation suitable for CAT-based administration with items of increasing difficulty based on target salience. We show feasibility in individuals with mental ages less than 24-months-old.nnCONCLUSIONS AND IMPLICATIONS: Tablet-based assessment of concept formation may be a useful outcome measure of an aspect of cognitive ability in young children. Future work will address optimizing the user interface and developing CAT administration. |
