My professional background reflects a strong trajectory for a career in interdisciplinary research as well as a commitment for diversity and inclusion within neuroscience. My long-term research goal is to develop measurable biomarkers and biologically plausible neural circuit models of abnormal social decision-making behavior in neurodevelopmental disorders to guide future intervention strategies. To achieve my research goals, I aspire to be an independent investigator at a research institution.
Postdoctoral Research with Dr. Kay Tye
Throughout the animal kingdom, social species establish social hierarchies and use social rank to guide the appropriate expression of dominance behaviors that are critical for survival. Neurobiological investigations have identified a key role for medial prefrontal cortex to lateral hypothalamus projection circuits in representing social ranks and mediating the expression of social dominance behaviors. The orbitofrontal cortex (OFC) has also been shown to process social information. OFC processes are thought to be mediated by vast neuromodulatory innervation from subcortical structures known to regulate sociability, such as the dorsal raphe nucleus (DRN). Serotonergic (5-HT) DRN neurons have been identified as a key neural substrate for mediating social interaction behaviors and they provide the majority of serotonergic innervation to the OFC. However, it is unclear whether DRN5-HT-OFC circuits can process social ranking information to influence behaviors dictated by social ranks.
My postdoctoral research aims to characterize the largely unexplored role of OFC in representing social ranks as well as reveal for the first time whether OFC interactions with serotonergic systems regulate the expression of social dominance behaviors during social competition. The central hypothesis of my project is that OFC encodes social ranking information during social competition and that serotonergic input from DRN modulates the expression of dominance behaviors. To test this, my research will use machine learning tools to automatically track and classify social competition behaviors in multiple animals. My research will then characterize behavioral states that are encoded by OFC neurons by measuring population dynamics aligned to classified social competition behaviors. Finally, experiments in this project will activate DRN5-HT-OFC projection terminals and establish how manipulating serotonergic circuit activity changes the expression of social dominance behaviors during social competition. Project findings will establish a novel, circuit-specific mechanism for how the brain processes social ranking information to adjust behavior accordingly during social competition. Developing a better understanding of the neuronal mechanisms governing the appropriate expression of social behaviors will provide great value to clinicians and translational researchers wanting to treat social behavior control deficits observed in psychiatric disease. Execution of these projects will be made possible by the Tye lab’s expertise in social behaviors and neural circuit dissection as well by expanding upon my prior training in calcium imaging, optogenetics, and computational analysis.
- Mills F, Lee CR, Howe JR, Li H, Shao S, Keisler MN, Lemieux ME, Taschbach FH,Keyes LR, Borio M, Chen HS, Patel RR, Gross AL, Delahanty J, Cazares C, Maree L, Wichmann R, Pereira TD, Benna MK, Root CM, Tye KM Amygdalostriatal transition zone neurons encode sustained valence to direct conditioned behaviors bioRxiv 2022.10.28.514263; doi: https://doi.org/10.1101/2022.10.28.514263
Graduate Research with Dr. Christina Gremel
Daily life involves making adaptive decisions to achieve desired goals. Alcohol dependence is associated with decision-making dysfunctions that are thought to drive a relapsing cycle of intoxication, bingeing, withdrawal and craving that promotes excessive alcohol use despite negative consequences. The orbitofrontal cortex (OFC) has been widely implicated in value-based, goal-directed decision-making and has been shown to be dysfunctional in alcohol-dependence. The first part of my thesis, funded by the NSF-GRFP, aimed to investigate whether alcohol dependence-induced changes in OFC function altered OFC representation of action and outcome-related neural activity. To do so, we used a well-validated model of alcohol dependence, chronic intermittent ethanol (CIE), and performed in vivo extracellular recordings as mice performed an instrumental lever-pressing task in which they self-initiated lever-press responses and were required to hold down the lever past a minimum duration to earn a food reward. We found that 1) alcohol dependence disrupted goal-directed action control of task performance, 2) increased OFC activity associated with lever-pressing actions, and 3) decreased OFC activity during outcome-related epochs. Our results suggested that chronic alcohol exposure induced long-lasting disruptions to OFC function such that activity associated with actions was enhanced, but OFC activity contributions to outcome-related information was diminished. Overall our findings identified some of the complexity in how OFC’s contributions to decision-making computations are altered following alcohol exposure and further supported the OFC as a target brain region for the intervention of alcohol use disorder (AUD).
While our previous findings implicated OFC in representing actions during decision-making, it remained unknown how whether OFC populations support action-related computations, including computations important for inferring past action information. Given that OFC has been hypothesized as key for inference-based Pavlovian behavior, the second part of my thesis aimed to investigate whether OFC populations contributed to action-related inferences. To do so, we took advantage of our self-paced lever-press hold down task to probe how current and inferred prior lever press durations guide subsequent lever press performance. We found that 1) calcium activity of genetically identified OFC subpopulations differentially instantiated current and prior action information during ongoing decision-making, 2) transient optogenetic disruptions to OFC activity left mice unable to use recently executed durations to guide ongoing action performance, and that 3) a chronic functional loss of OFC circuit activity resulted in a compensatory mechanisms of repetitive action control, increasing behavioral reliance on the just completed action. Thus our results identified a novel role for OFC in the continuous integration of inferred action information in guiding adaptive behavior.
My thesis work thus far suggests OFC populations differentially contribute to actions during decision-making, and that such computations are disrupted in alcohol dependence. The final part of my thesis examined which OFC projections are important for behavioral control. OFC projects to secondary motor cortex (M2) and this circuit has been implicated in compulsive disorders and repetitive behaviors, including AUD. Thus far, we have found chronic alcohol exposure disrupts premotor circuits by altering cortico-cortical transfer of information about actions and their outcomes, thus providing mechanistic support for targeting activity of human premotor regions as a potential treatment in AUD.
- Schreiner D, Renteria R, Baltz ET, Cazares C, Gremel, CM (2022, in Review) Chronic alcohol exposure alters decision-making strategy via hyperactive premotor corticostriatal activity. Cell Reports.
- Cazares C, Schreiner DC, Valencia ML, Gremel CM. (2022) Orbitofrontal cortex populations are differentially recruited to support actions. Curr Biol. Nov 7;32(21):4675-4687.e5. doi: 10.1016/j.cub.2022.09.022. Epub 2022 Oct 3. PMID: 36195096; PMCID: PMC9643660.
- Schreiner D, Cazares C, Renteria R, Gremel, CM (2022) Information normally considered task-irrelevant drives decision-making and affects premotor circuit recruitment. Nat Commun. Apr 19;13(1):2134. doi: 10.1038/s41467-022-29807-2. PMID: 35440120; PMCID: PMC9018678.
- Yalcinbas, E. A., Cazares C., Gremel, C.M. (2021) Call For A More Balanced Approach to Understanding Orbital Frontal Cortex Function. Behavioral Neuroscience. 2021 Apr;135(2):255-266.
- Cazares C., Schreiner D., Gremel, C.M. (2021) Different Effects of Alcohol Exposure on Action and Outcome Related Orbitofrontal Cortex Activity. eNeuro. 2021 Mar PMID: 33785522.
- Renteria R., Cazares C., Baltz E.T., Schreiner D.C., Yalcinbas E.A., Stainkellner T., Hnasko T.S., Gremel, C.M. (2021) Mechanism for differential recruitment of orbitostriatal transmission during actions and outcomes following chronic alcohol exposure. Elife. 2021 Mar 17;10:e67065. doi: 10.7554/eLife.67065. PMID: 33729155.
- Renteria R., Cazares C., Gremel C.M. (2020) Habitual Ethanol Seeking and Licking Microstructure of Enhanced Ethanol Self-Administration in Ethanol-Dependent Mice. Alcohol Clin Exp Res. 2020 Feb 4. doi:10.1111/acer.14302.
Post-baccalaureate Research with Dr. Irwin Lucki and Dr. Brian Litt
To better prepare for a Ph.D. in Neuroscience, I joined Dr. Irwin Lucki’s lab at the University of Pennsylvania through the Postbaccalaureate Research Education Program (PennPREP). My training built a familiarity with animal handling and molecular neurobiology. More importantly, it was the first time my research centered around proposed neurobiological mechanisms of disrupted behavior in pathological conditions, a topic that became the thematic foundation for my NSF-GRFP award in 2016. This influential experience led to
an interest in developing a long-term research plan that aimed to guide the development of therapeutics for mental disorders. My 2nd year in PennPREP was spent in Dr. Brian Litt’s lab to cultivate my background in computational neuroscience and to learn how impaired cognition manifests in neurological disorders. With this formative experience, I set off to UC San Diego to earn a neuroscience Ph.D. with the long-term career goal of becoming an interdisciplinary neuroscientist that combined neurobiological and computational approaches to study cognitive processes and behavior in healthy and pathological conditions.
- Ung H., Cazares C., Nanivadekar A., Kini, L. Wagenaar J., Becker D., Kahana M., Sperling M., Sharan A. Lucas T., Baltuch G., Litt B., Davis K.A. (2017) Interictal Epileptiform Activity outside the Seizure Onset Zone Impacts Cognition. Brain, Volume 140, Issue 8, 1 August 2017, 2157:2168
Undergraduate Research with Dr. Richard Ivry and Dr. Ted Zanto
My introduction to academic research occurred when I joined Dr. Richard Ivry’s lab at UC Berkeley. My research focused on investigating how preparatory anticipation of decision-making actions influenced corticospinal excitability. Our results showed that levels of corticospinal excitability during response inhibition correlated with the anatomy of available response choices and suggested a functional role for the corticospinal
tract in mediating the preparation of decision-making actions. My ability to communicate science grew by presenting my findings at multiple national research conferences and by participating as a co-author for three research article publications. Dr. Ivry’s unwavering support further motivated me to complete a cum laude honors thesis and set foundational training in behavioral paradigms and computational analysis, setting off my research trajectory towards understanding how the central nervous system controls behavior. The MARC program funded a Summer position with Dr. Ted Zanto in Dr. Adam Gazzaley’s lab at UC San Francisco. My project focused on investigating the effects of aging on multitasking ability in a longitudinal videogame cognitive training study. Our results suggested that aged participants who became more proficient at multitasking recruited a prefrontal
network critical for the control of behavior in comparison to underperformers. My time at UCSF was key for nurturing a desire to study how disrupted cognition impairs executive function and behavior.
- Labruna, L., Tischler C., Cazares C., Greenhouse I., Duque J., Lebon F., Ivry RB. (2019) Planning face, hand, and leg movements: anatomical constraints on preparatory inhibition. J. Neurophysiol. 121, 1609:1620
- Duque J., Labruna L., Cazares C., Ivry R. (2014) Dissociating the influence of response selectionand task anticipation on corticospinal suppression during response preparation. Neuropsychologia 65:287:296
- Labruna L., Lebon F., Duque Julie., Klein P-A., Cazares C., Ivry R. (2014) Generic inhibition of the selected movement and constrained inhibition of non-selected movements during response preparation. Journal of Cognitive Neuroscience 26:2, 269:278