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					                                                                        David R. Vago, Research Statement         1
General interests and research goals.
My research interests broadly focus on the neurobiological foundations of learning, memory, and cognitive and
emotional control. The following set of fundamental questions should summarize the overarching goals of my
research:

   A. Generally speaking, what aspects of our previous experiences influence our future cognitive and
      emotional processes and associated behaviors?
   B. What are the functional dynamics in which neuroanatomical and neuromodulatory pathways interact in
      terms of mnemnonic function and dysfunction?
   C. More specifically, how do the anatomical, physiological, and neuropharmacological correlates of the
      processes associated with mnemonic function (i.e., encoding, consolidation, and retrieval) operate in
      relation to ongoing cognitive and emotional processes?

I have adopted a translational perspective using multiple converging methods of research to provide a means
of testing specific models of function and dysfunction at the computational, neurophysiological, and behavioral
levels. Below, I review my past and current research activities and elaborate upon the methods I have used, or
am actively using, to answer these fundamental questions. In addition, I attempt to demonstrate how these
questions can apply to critical issues in the cognitive neurosciences beyond the scope of learning and memory,
but also in relation to the neurobiology of sleep, schizophrenia, affective disorders, and mind-body interactions.

Research experience.
1. How do sleep and circadian rhythms affect memory reconstruction and associated neural plasticity
in hippocampal circuitry?

Lab: Division of sleep medicine, Harvard Medical School, Brigham and Women's hospital
Supervisor: Charles Czeisler, PhD
Position: Research assistant/Lab technician
Time period: 1993
Methods and Techniques: Polysomnography and EEG recording; Clinical research training
Research Description: I was involved in the collection of data that lead to the publication of Use of Bright
Light to Treat Maladaptation to Night Shift Work and Circadian Rhythm Sleep Disorders (Czeisler & Dijk,
1995). It was found that exposure to bright light may cause the circadian system to shift to any desired phase
causing sleep disturbances in shiftworkers. Furthermore, night exposure to bright light can virtually eliminate
circadian maladjustment among night workers.

Lab: Sleep Disorders Institute, St. Lukes-Roosevelt hospital, Columbia University.
Supervisor: Gary Zammit, PhD
Position: Lab technician/Research assistant
Time period: 1997-1999
Methods and Techniques: Polysmonography and EEG recording; Clinical research training
Research Description: I furthered my understanding of sleep disorders (e.g., apnea, periodic limb movement
disorder, restless legs syndrome, narcolepsy, REM-behavior disorder) by conducting comprehensive scoring
and analysis of EEG records. This experience in a clinical setting gave me great perspective in applied
cognitive neurosciences. I was involved in collecting data investigating differences in cognitive performance
after middle-of-the-night administration of either Zaleplon or Zolpidem. This led to the publication of “Zaleplon
vs. Zolpidem: Difference in Next-Day Residual Sedation After Middle-of-the-Night Administration”, (Zammit,
2000).

A growing body of evidence has implicated sleep and associated circadian and neuroendocrine function in the
consolidation of learning and memory processes. There is also evidence demonstrating that a disruption to
circadian function has direct effects on cellular and molecular factors underlying normal motivational and
emotional states. My experience in the Czeisler lab and at the Sleep Disorders Institute stimulated my interest
in how the cellular and molecular changes in anatomical structures underlying memory formation and retrieval
(i.e., hippocampus, pre-frontal cortex) may interact with circadian regulation and sleep architecture.
                                                                         David R. Vago, Research Statement       2
2. Can we develop realistic computational and systems-level models of the hippocampus?

Lab: Cognitive Neurobiology Laboratory, Dept. of Psychology, University of Utah
Supervisor: Gene Wallenstein, Ph.D.
Position: Graduate student
Time Period: 1999-2001
Methods and Techniques: Computational modeling; Molecular and systems-level behavioral pharmacology
Research Description: I began to study the hippocampus and its contribution to the modulatory mechanisms
underlying contextual (i.e., spatial/temporal), and working types of memory formation and retrieval. We
developed realistic computational and systems-level models for hippocampal function. Our conceptual model
of the hippocampus was published in the Encyclopedia of Neurological Sciences (Wallenstein, Vago, &
Walberer, 2001). In this work, I observed very specific temporal dynamics and anatomical contributions to
encoding and retention function. On a molecular level, we assessed the temporal dynamics involved in the
cascade of molecular markers of early and late phase long-term potentiation (LTP), protein phosphorylation,
and gene transcription. We demonstrated that a significant consolidation deficit of long-term contextual fear-
conditioning memory is maximal when protein kinase C (PKC) and cAMP-dependent protein kinase (PKA) are
inhibited at 90 min post-conditioning (Wallenstein, Vago, & Walberer, 2002). These results suggest the
existence of a critical time window during which these enzymes must be activated for the consolidation of long-
term memories. In addition, it suggests a time-limited role for the hippocampus in terms of contextual memory
consolidation.

3. What are the temporal dynamics of contextual memory formation and consolidation at a
pharmacological level?

I conducted my Master's thesis research on the effects of nicotinic and muscarinic acetylcholine receptor
antagonists on the acquisition and consolidation of contextual fear conditioning. We demonstrated a dose-
dependent deficit in both acquisition and consolidation when a muscarinic antagonist, scopolamine is infused
intracranially into the dorsal hippocampus either 15 minutes pre-conditioning or multiple infusions post-
conditioning (1 min, 24 hrs, 48 hrs) (Wallenstein, & Vago, 2001).

Lab: Cognitive Neurobiology Laboratory, Dept. of Psychology, University of Utah
Supervisor: Raymond P. Kesner, Ph.D.
Position: Graduate student
Methods and Techniques: Systems-level behavioral pharmacology; In vivo electrophysiology
Research Description: Under the supervision of Ray Kesner, we found that both the pre- and post-
conditioning infusion of nicotinic antagonists, MLA (methyllycaconitine; α-7 nicotinic antagonist) and
mecamylamine (non-selective nicotinic antagonist) into the dorsal hippocampus impaired contextual
conditioning. Interestingly, there were specific differences between effects of the drugs. MLA disrupted
retention when administered 1 min or 6 hrs post-conditioning; whereas, mecamylamine disrupted retention
when administered 15 min before or 1 min post-conditioning (Vago & Kesner, 2007). These differences
suggested that specific nicotinic receptor subtypes are involved in different phases of contextual memory
consolidation.

4. What are the neuromodulatory pathways underlying specific memory attributes?

As a doctoral candidate in the Kesner lab, I furthered my investigation of memory and the underlying
anatomical and pharmacological correlates of memory by utilizing the Kesner attribute model. This model
proposes that memory organization is based on functionally separate but interdependent attributes of memory,
such as, space, time, response, affect, and sensory perception in animals and human primates that are
associated with different neuroanatomical substrates. I investigated the neuroanatomical and neuromodulatory
pathways underlying these specific attributes for mnemnonic function and in some cases focused directly on
the differences between encoding and retrieval function using behavioral pharmacology, while also attempting
to characterize modulatory effects using in vivo electrophysiology. I became particularly interested in a model
of dopaminergic function that relates to differential modulation of the intrinsic circuitry of the hippocampus. It
was recently suggested that relative to the intrinsic tri-synaptic circuitry, the direct cortical input to the CA1
                                                                        David R. Vago, Research Statement         3
region of the hippocampus is selectively modulated by dopamine, such that a hyperactive dopaminergic
system may produce selective dysfunction in this direct projection (i.e., perforant path) and subsequently
produce selective impairments in hippocampal function. My research has investigated the functional
contribution of this pathway by infusing a non-selective dopamine agonist (apomorphine) directly into the CA1
subregion during learning and memory tasks that have previously been shown to be CA1-dependent. Our
results explicitly parallel previous findings associated with CA1 dysfunction and suggest that increases in
dopamine availability and receptor function produce specific interference in CA1-dependent behavior (i.e.,
intermediate-term working memory, retrieval of spatial and context-associated information, and match-
mismatch/novelty detection for objects and spatial information). One may further speculate that the observed
deficits can be attributed to apomorphine acting on CA1-specific dopamine receptors to disrupt the direct
perforant pathway and isolate the hippocampus from receiving direct sensory input from the entorhinal cortex
(EC). Such research suggests that dopamine plays an important modulatory role in many forms of memory
processing and has raised the possibility of a more fundamental role for EC—CA1 synaptic transmission. In
terms of hippocampal-cortical circuitry, my current findings have implications for understanding differences in
novelty/familiarity processing and the sensory processing deficits associated with dopaminergic hyperfunction
in disorders such as schizophrenia or amphetamine psychosis (Vago, Bevan, & Kesner, 2007).

Current research.
5. Can mindfulness meditation training facilitate behavioral and neural plasticity in terms of cognitive
and emotional control?

Lab: Utah Center for Exploring Mind-Body Interactions (UCEMBI), University of Utah, Pain Research Institute.
Supervisor: Yoshio Nakamura, Ph.D.
Position: Post-doctoral research associate
Time period: September, 2005 - current
Methods and Techniques: patient-oriented research; mindfulness meditation research; functional imaging
technology (HD EEG, fMRI, MEG)
Research Description: I have been working on a pilot project funded by UCEMBI and the Mind and Life
Institute, in collaboration with Yoshi Nakamura and other UCEMBI affiliated investigators. Through my
participation in the project, I have learned the necessary skills for neuroimaging (HD EEG, fMRI, MEG), and
have acquired sufficient background for conducting clinical and cognitive neuroscience research with human
subjects. I have been responsible for designing two separate research protocols, applying for grant support as
the Principal Investigator from both the Mind and Life Institute and Utah Magnetic Source Imaging, as well as
conceptualizing and implementing the proposed laboratory-based cognitive measures.

I have personal interests in Eastern philosophy that led me to apply to the Mind and Life Summer Research
Institute in 2005, at which time I began integrating these interests into my scientific research. I received the
2006 Varela Grant Award from the Mind and Life Institute (mindandlife.org) to investigate cognitive and
emotional processes in two groups of fibromyalgia patients: fibromyalgia patients with meditation experience
(FMM) and fibromyalgia patients without any prior meditation experience (FM). Specifically, the objectives of
the ongoing pilot study have been: 1) to observe patterns of event-related brain activity (using HD-EEG and
MEG), and startle response (i.e., eyeblink magnitude) associated with the processing of affective visual stimuli
and acoustic startle in an emotion-potentiated startle paradigm, 2) evaluate performance (reaction time)
differences between FM and FMM participants in paradigms testing alerting, orienting, engagement, and
disengagement of attention, 3) explore patterns of brain activity in anticipation of, and in response to, painful
stressors (i.e., acute pressure pain) during conditions of varied levels of certainty, using functional magnetic
resonance imaging (fMRI), and 4) investigate qualitative, cognitive, and affective changes associated with
mindfulness meditation training using qualitative measures.

Future Directions.
It appears that memories for specific attributes or dimensions are not represented by any single neural region,
but rather by extensive interconnected neural circuitry. In the Kesner lab, I have explored the multiple
dimensions associated with memory through an arsenal of behavioral paradigms. For example, I have
assessed short-term, working, intermediate-or long-term memory and memory for temporal order using the
dry-land version of the water maze, and radial 8-arm maze. I have assessed encoding and retrieval
                                                                          David R. Vago, Research Statement        4
mechanisms using the fear conditioning paradigm and the modified Hebb-Williams maze. I have also used
paired associate learning, detection of novelty, and/or variations on a reaction-to-change task to assess other
forms of mnemonic function. Through the use of specific lesion and pharmacological analyses, research from
the Kesner lab up to the present has revealed interesting subregional differences within the hippocampus,
surrounding subiculum, entorhinal and pre-frontal cortices. The attribute model suggests a need to further
explore the interactions among all anatomical substrates that mediate specific dimensions of memory
processing and how they may contribute differently to the representation of past experiences and plasticity
associated with novel types of stimuli.

My more recent use of imaging techniques has provided me with additional tools to pursue this line of
research. As I alluded to earlier, I aim to investigate the neural correlates associated with mnemonic processes
in relation to adaptive (e.g., attention, emotion-regulation, sleep) and maladaptive (e.g., attention-deficit,
anxiety, sleep-interruption) cognitive and emotional states in which dimensions of memory are most
susceptible to influence. It is clear that memory is a tool for learning from our mistakes, filtering, and organizing
the onslaught of multimodal sensory, cognitive, and affective processing resulting from our everyday
experience; what remains, however, is the identification of the time-specific pattern of neurochemical and
physiological changes associated with the encoding, consolidation, and recall of our experiences and
integration with our ongoing and future behavior. My long-term program of research aims to clarify these
interactions using converging methods of physiological and functional neuroimaging techniques in humans
paralleled by the use of in vivo electrophysiology and behavioral pharmacology in the rat animal model. Such
research will have implications for understanding the behavioral manifestations of dysfunctional states (i.e.,
affective disorders, memory-related cognitive deficits, disruption in cognitive control) and furthering our
understanding of mind-brain interactions.


References.
Czeisler C.A., Dijk D.J. (1995) Use of bright light to treat maladaptation to night shift work and circadian
       rhythm sleep disorders. Journal of Sleep Research 4:70-73.

Wallenstein G.V., Vago, D.R. (2001) Intrahippocampal Scopolamine Impairs Both Acquisition and
      Consolidation of Contextual Fear Conditioning. Neurobiology of Learning and Memory, 75, 245- 252.

Wallenstein G.V., Vago D.R., Walberer A.M. (2002) Time-dependent involvement of PKA/PKC in
      contextual memory consolidation. Behavioural Brain Research, 133, 159-164.

Vago D.R., Kesner R.P. (2007) The role of the direct perforant path projection to the dorsal CA1
      subregion in memory retention and retrieval. Hippocampus.

Vago D.R., Kesner R.P. (submitted August, 2007) The role of the direct perforant path projection to the dorsal
      CA1 subregion in intermediate-term working memory and spatial change. Behavioural Brain Res.

Vago D.R., Kesner R.P. (2007) Cholinergic modulation of Pavlovian fear conditioning in rats: Differential
      effects of intrahippocampal infusion of mecamylamine and methyllycaconitine. Neurobiology of
      Learning and Memory, 87, 441-449.

Zammit G. (2000) Zaleplon vs. Zolpidem: Difference in Next-Day Residual Sedation After Middle-of-the-Night
      Administration. The European Sleep Research Society, Istanbul, Turkey.

				
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