Graduate Research with Dr. Christina Gremel

Previous work has shown that alcohol abuse alters the computations performed in neural circuits supporting goal-directed control of decision-making actions, resulting in maladaptive behaviors thought to increase the vulnerability to relapse. While neurobiological investigations have identified a key role for orbitofrontal cortex (OFC) computations in goal-directed decision-making, the specific neural mechanisms underlying these computations and their disruption in alcohol addiction remain unknown. For my first project, I assessed how chronic alcohol exposure results in a protracted disruption of decision-making processes by employing a well-validated chronic intermittent ethanol (CIE) model to induce ethanol dependence in mice. To examine potential dependence-induced disruptions to OFC computations performed during decision-making, I used in vivo extracellular recording techniques in conjunction with an instrumental task where a mouse must hold a lever press down for a minimum duration in order to get a reward. Prior induction of ethanol dependence led to an insensitivity to outcome devaluation, indicative of a loss of goal-directed control over lever press behavior. I also found that OFC populations differentially encoded decision-making planning, ongoing execution, and outcome evaluation in a dynamic manner, and that these cortical representations were significantly altered in ethanol dependent mice. My results confirmed that ethanol dependence can lead to a loss of goal directed control over decision-making behavior and suggested that altered OFC modulation during active decision-making may be a strong contributor of goal-directed deficits observed in alcohol dependence. During this time, I also collaborated with a postdoc in the lab to study the dissociation in behavioral mechanisms between decision‐making and consumption phenotypes associated with ethanol dependence.

While my dissertation work has so far established that alcohol-depended perturbs dynamic OFC encoding of decision-making actions, the biological mechanism by which these changes occur remains unclear. Identification of neural circuit changes that contribute to alcohol dependence-induced deficits in flexible decision-making have been constrained by a lack of robust exploratory methodology. For example, most research focused on circuit function has relied on a priori assumptions about candidate regions and their known input-output mappings. Given the vast complexity of the circuit mechanisms that support decision-making, unbiased approaches can pose an advantage for identifying the dependence-induced changes that result in aberrant decision-making behavior. For the remainder of my thesis, I am employing state-of-the-art monosynaptic rabies tracing to look at how alcohol dependence redistributes whole-brain input connectivity into the OFC. In addition, I am using in-vivo optical measures of activity in genetically identified OFC sub-populations to unravel the neural mechanisms through which alcohol dependence disrupt ongoing decision-making computations.

  • Cazares C., Schreiner D., Gremel, C.M. (2021) Different Effects of Alcohol Exposure on Action and Outcome Related Orbitofrontal Cortex Activity. eNeuro. 2021 Mar 30:ENEURO.0052-21.2021. doi:10.1523/ENEURO.0052-21.2021. Epub ahead of print. 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

In the Lucki Lab at the University of Pennsylvania, I used animal models of depression and anxiety to evaluate the efficacy of novel neurotransmitter and peptide receptor ligands for clinical therapeutic effects. My main project focused on evaluating the therapeutic potential of a novel, highly selective kappa-opioid receptor (KOR) antagonist (LY23456302) in an animal model of co-morbid depression and anxiety, Unpredictable Chronic Mild Stress. My results showed that chronic, selective blockage of KORs led to reduced depressive-like behavior quicker than typically prescribed antidepressants, supporting the development of novel, selective KOR antagonists for treatment-resistant depression and anxiety disorders. My time in the Litt Lab at UPenn was spent investigating the cause of cognitive deficits often reported by medically refractory epilepsy patients. For my project, we hypothesized that interictal epileptiform spikes, which are routinely seen in intracranial electroencephalography (iEEG) of epilepsy patients, impaired memory processes in an anatomically constrained manner. To investigate this, I analysed iEEG recordings from over sixty epilepsy patients performing a delayed free recall task used to test short-term memory. I built a data analysis pipeline that quantified the effect of each interictal spike on the probability of successful recall using a generalized logistic mixed model. My main finding was that in patients with left lateralized seizure onset zones, spikes outside the seizure onset zone impacted memory encoding, whereas those within the seizure onset zone did not. My results suggested that seizure onset regions are generally dysfunctional at baseline and support the idea that interictal spikes disrupt cognitive processes with respect to the anatomical distribution of the underlying tissue.

  • 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. Adam Gazzaley

During my undergraduate years at UC Berkeley, my projects focused on investigating how corticospinal excitability during decision-making actions is shaped by anticipation and available choices. In our daily life, we are faced with a variety of response choices during decision making (e.g. do I flip a light switch with my right or left hand?). What are the motor inhibitory mechanisms that optimize our responses? In the Ivry lab, I learned how to apply Transcranial Magnetic Stimulation (TMS) over the motor cortex of participants engaged in a delayed choice reaction time (RT) task. Each TMS pulse elicited a motor evoked potential (MEP) measured by electromyography recordings over response choices (i.e. left or right hands). In my first project, I found that corticospinal excitability during response inhibition varied as a function of anticipation, possibly to prevent the occurrence of premature and inappropriate responses during competitive action selection. I also conducted a set of experiments that assessed the role of corticospinal excitability in the context of competing actions between homologous or non-homologous muscles, upper and lower limbs, and body parts rarely involved in action competition (e.g. head). My results showed that levels of corticospinal excitability during response inhibition changed as a function of the anatomy of response choices, suggesting that motor response inhibition is constrained less by the similarity between potential responses (i.e. homology), and perhaps more by a past history of competitive interactions (e.g. we rarely have to choose between right finger vs head movements in our daily decision-making). During the summer of 2013 in the Gazzaley Lab at UC San Francisco, I used a computational approach to analyze attention-related electroencephalographic activity from aged participants of a longitudinal videogame cognitive training study that assessed multitasking performance. My project involved using sLORETA and Matlab to localize the source of midline frontal theta (MFT) activity occurring shortly after distractors appeared on the screen. I found that MFT power increases across training were localized to the medial frontal gyrus, a brain region critical for sustained attention. Moreover, my results showed that MFT power decreases across training occurred in the motor cortex, suggesting that as aged participants became more proficient at multitasking, a vast prefrontal network critical for executive control was recruited to a greater degree than regions involved in the initial motor skill adaptation of multitasking demands.

  • 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
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