Velázquez, Cristina, PhD

Adjunct Professor

Associate Investigator at the Institute of Neurobiology

Dr. Cristina Velázquez

Contact Info

Research Interests

CNS plasticity in response to substance abuse.

Alcoholism has devastating effects on individuals and society as a whole. Alcohol tolerance is a key factor leading to increased consumption and subsequent alcohol abuse and alcoholism. Our goal is to understand, at the molecular level, the adaptations that occur in response to alcohol exposure that underlie tolerance and its effects on consumption. Current projects explore key regulated processes triggered during rapid ethanol exposure underlying persistent changes in neuronal excitability, thus providing insights into the mechanism of molecular tolerance and its behavioral consequences.

Experimental Techniques:

  • Electrophysiology
  • Molecular Biology / Proteomics
  • Computational Modeling
  • Cellular and Neuronal Cultures
  • Confocal Microscopy
  • Behavioral Assays

Main Project: Alcohol Tolerance via Wnt/ß-catenin impacts BK expression and subsequent ethanol consumption.

Specific Aim 1. Hypothesis: BK channel internalization in response to 6hr ethanol exposure is protein synthesis-dependent in neurons.

Of particular interest will be the compartmentalized expression and protein synthesis-dependent regulation of these endogenous BK channels and their possible effects on specific neuronal synaptic inputs. We will thus determine the total and membrane expression of BK channels on cell bodies, processes and synapses, utilizing TIRF microscopy and epifuorescent multichannel confocal microscopy, of both striatal and hippocampal neurons in response to ethanol and its dependence on de novo protein synthesis.

Specific Aim 2. Hypothesis: De novo synthesis, of proteins mediating the Wnt/ß-catenin signaling pathway, is upregulated in response to 6hr alcohol exposure in neuronal preparations.

Identification and quantification of neuronal de novo synthesized proteins will allow us to determine specific profiles of protein expression in response to ethanol exposure allowing for a more comprehensive view of possible regulatory mechanisms. Further analysis of all significantly translated proteins by Ingenuity Pathway Software will likely identify pathways yet unassociated to the neuronal ethanol response, which remain to be explored as potential therapeutic targets.

Specific Aim 3. Hypothesis: Wnt/β-catenin signaling pathway is responsible for alcohol-induced BK channel internalization resulting in increased intrinsic neuronal excitability.

Tolerance is a distinct form of neuronal plasticity, which we hypothesize, involves changes in intrinsic excitably via internalization of BK channels in neurons resulting in ethanol-associated homeostatic counter-adaptations that lay the ground work for future alcohol abuse and dependence. Preliminary studies on non-neuronal preparations result in internalization of the BK observed as a decrease in current density, which is regulated by the Wnt/β-catenin signaling pathway. Similar results were observed with hippocampal neurons. Therefore, we will now focus on understanding the impact of ethanol-induced BK channel internalization on intrinsic excitability as a function of fAHP and firing frequency using striatal and hippocampal neurons known to play a key role in alcohol abuse and dependence.

Specific Aim 4. Hypothesis: Pre-exposure to EtOH for 6hrs increases subsequent EtOH voluntary consumption in mice which can be blocked via clinically tested Wnt/β-catenin inhibitors.

We hypothesize that significant changes in BK channel surface expression due to 6hr EtOH exposure triggers a behaviorally relevant form of molecular tolerance to alcohol, which leads to subsequent increases in voluntary alcohol consumption. Therefore, altering key steps in the development of this form of tolerance may delay or prevent changes in alcohol consumption due to tolerance. The experimental approach to test this hypothesis is facilitated by the existence of several clinically tested Wnt/β-catenin signaling pathway inhibitors, currently used on humans solely for cancer treatment, now available to explore a unique therapeutic target for the treatment and prevention of alcoholism.

Present Funding

NIH R01

Selected Publications:

  • Kolpakova J, van der Vinne V, Giménez-Gómez P, Le T, You IJ, Zhao-Shea R, Velazquez-Marrero C, Tapper AR, Martin GE (2021) Binge Alcohol Drinking Alters Synaptic Processing of Executive and Emotional Information in Core Nucleus Accumbens Medium Spiny Neurons. Front Cell Neurosci. 2021 Nov 16;15:742207. doi: 10.3389/fncel.2021.742207. PMID: 34867199; PMCID: PMC8635139.
  •  Velazquez-Marrero C, Custer EE, Marrero H, Ortiz-Miranda S, Lemos JR (2020) Voltage-induced Ca2+ reléase by ryanodine receptors causes neuropeptide secretion from nerve terminals. J Neuroencorinol Apr; 32(4):e12840 doi: 10.1111/jne.12840. PMID: 32227430
  • Velázquez-Marrero C, Burgos A, García JO, Palacio S*, Marrero HG, Bernardo A, Pérez-Laspiur J, Rivera-Oliver M, Seale G, Treistman SN (2016) Alcohol regulates BK Surface expression via Wnt/b-catenin signaling. J Neurosci (Oct 12) 36(41):10625-10639.
  • Palacio S, Velázquez-Marrero C, Marrero HG, Seale GE, Yudowski GA, Treistman SN (2015) Time-dependent effects of ethanol on BK channel expression and trafficking in hippocampal neurons. Alcohol Clin Exp Res, in press (PMID:26247146).
  •  Velázquez-Marrero C, Seale GE, Treistman SN, & Martin GE (2014) Large conductance voltage- and Ca2+-gated potassium (BK) channel b4 subunit influences sensitivity and tolerance to alcohol by altering its response to kinases. J Biol Chem. 289(42):29261-29272.
  • Velázquez-Marrero C, Ortiz-Miranda S, Marrero HG, Custer EE, Treistman SN, Lemos JR (2014) mu-Opioid inhibition of Ca2+ currents and secretion in isolated terminals of the neurohypophysis occurs via ryanodine-sensitive Ca2+ stores. J Neurosci, 34(10), 3733-3742.
  • C Yuan, C Velázquez-Marrero, A Bernardo and SN Treistman (2014) Lipids modulate the increase of BK channel calcium sensitivity by the beta1 subunit. PLoS One, 2014. 9(9): p. e107917
  • Lemos JR, Ortiz-Miranda SI, Cuadra AE, Velázquez-Marrero C, Custer EE, Dad T, et al. (2012) Modulation/physiology of calcium channel sub-types in neurosecretory terminals. Cell Calcium, 51(3-4), 284-292.
  • Velázquez-Marrero C, Wynne P, Bernardo A, Palacio S, Martin G, Treistman SN (2011) The relationship between duration of initial alcohol exposure and persistence of molecular tolerance is markedly nonlinear. J Neurosci, 31(7), 2436-2446.
  • Ortiz-Miranda SI, Dayanithi G, Velázquez-Marrero C, Custer EE, Treistman SN, Lemos JR (2010) Differential modulation of N-type calcium channels by micro-opioid receptors in oxytocinergic versus vasopressinergic neurohypophysial terminals. J Cell Physiol, 225(1), 276-288.
  • Velázquez-Marrero CM, Marrero HG, Lemos JR (2010) Voltage-dependent kappa-opioid modulation of action potential waveform-elicited calcium currents in neurohypophysial terminals. J Cell Physiol, 225(1), 223-232.
  • Knott TK, Velázquez-Marrero C, Lemos JR (2005) ATP elicits inward currents in isolated vasopressinergic neurohypophysial terminals via P2X2 and P2X3 receptors. Pflugers Arch, 450(6), 381-389.
  • De Crescenzo V, ZhuGe R, Velázquez-Marrero C, Lifshitz LM, Custer E, Carmichael J, et al. (2004) Ca2+ syntillas, miniature Ca2+ release events in terminals of hypothalamic neurons, are increased in frequency by depolarization in the absence of Ca2+ influx. J Neurosci, 24(5), 1226-1235.
  • Velázquez-Marrero, J Lemos, (2000) Cuba. Published online: http://www.ciencia.cl/CienciaAlDia/, J. Golowasch, editor and chief. (The article highlights the efforts of members of the Society for Neuroscience to incorporate the Cuban scientific community, via scientific exchange, with the world. These efforts lead to a pioneer satellite Neuroscience meeting in Havana, Cuba on October 20-23, 1999.)

In-Progress:

  • C Velázquez-Marrero, G Seale, J García, S Palacio, A Bernardo, and SN Treistman. Molecular tolerance of the αBK channel after 6hr alcohol exposure is protein synthesis dependent. Process of pre-submission to Neuron.
  • Velázquez-Marrero C, Palacio S, and Treistman SN. BK channel trafficking in response to alcohol is dependent on miRNA9 recognition site on the 3”UTR sequence.
  • Garrett E. Seale, Cristina Velazquez-Marrero, Jose Garcia, Stephanie Palacio, Marla Rivera, Guillermo Yudowski, Steven N. Treistman. Compartmentalized Regulation of BK Channel Distribution at Synapses by Ethanol.