University of Vermont

Neuroscience Graduate Program

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RESEARCH

PUBLICATIONS

COLLABORATIONS

RESOURCES

Research

Project 1:  How does serotonin modulate brain regions associated with anxiety-like behavior?

Substantial evidence suggests that the activation of serotonin systems alters anxiety-like behavior; however, the nature of the relationship between serotonin and anxiety is still unclear.  For example, selective-serotonin reuptake inhibitors (SSRIs), which elevate levels of serotonin in the central nervous system, have well-known therapeutic anxiety-reducing effects when administered chronically.  But the acute effects of these drugs often include increases in indices of anxiety.  Several nuclei associated with the central extended amygdala, including the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA) have been suggested to mediate fear/anxiety-like behavior.  We are currently using behavioral, anatomical, and physiological techniques to determine how these brain regions respond to serotonin, in order to better understand the relationship between serotonin and anxiety.  Specific questions include:

  • Using brain microinfusion techniques combined with behavioral assays of anxiety, how does the activation/inactivation of specific serotonin receptor subtypes within the BNST alter anxiety-like behavior in the social interaction test, elevated plus maze, and acoustic startle response?
  • Using brain microinfusion techniques combined with immunohistochemistry, how does pharmacological activation of the serotonergic dorsal raphe nucleus alter activity in the central extended amygdala (as measured by c-fos expression)?
  • Using whole-cell patch clamp electrophysiology, how do BNST neurons respond to serotonin?  What receptors and effector systems mediate this response?

Project 2:  How does voluntary exercise modulate brain regions associated with anxiety-like behavior

Exercise is therapeutic in the treatment of anxiety, and the effects of exercise may be mediated through changes in serotonin functioning.  We are currently investigating whether the effects of exercise on anxiety are mediated by serotonin changes in the BNST.  Metachlorophenylpiperazine  (mCPP), which is an agonist at 5-HT2B and 5-HT2C receptors (with some affinity at 5-HT2A receptors), increases signs of anxiety in both humans and animals.  The BNST has been implicated in mediating anxiety in a number of paradigms in rodents and primates.  Therefore, the BNST might an important brain region mediating the effects of serotonergic modulation on anxiety.  Single BNST neurons can respond to 5-HT with excitation and/or inhibition, and mCPP injected into the BNST is anxiogenic likely because this drug selectively activates the excitatory response on these neurons, which is mediated, in part, by the 5-HT2 family of receptors.  Consistent with reports in humans, we have shown that voluntary exercise is anxiolytic in many anxiety models in animals.  Importantly, voluntary exercise reduces the increases in anxiety observed after mCPP. These studies are being conducted in a collaborative effort with Professor Bill Falls and the Falls Laboratory in the Department of Psychology. Specific question include:

  • Using brain microinfusion techniques combined with behavioral assays of anxiety, are the effects of intra-BNST mCPP mediated by 5-HT2A or 5-HT2C receptors?
  • Does voluntary exercise on the dose-response curve of intra-BNST mCPP?
  • Using whole-cell patch clamp electrophysiology, Does voluntary exercise shift the population of serotonin responses to the favor inhibition, and does exercise alter the dose-response curve to exogenously applied mCPP?

Funded by a grant from the National Institute of Mental Health

Project 3:  How do pituitary adenylate cyclase-activitating polypeptides modulate anxiety-like behavior?

Although evidence suggests that chronic stress is important to the etiology of anxiety disorders, ,the mechanisms by which stress alters brain anxiety circuits are still unknown.  Substantial evidence has implicated the BNST as a critical structural node mediating anxiety-like behavior in humans and animals.  The BNST organizes central and peripheral stress responding to unpredictable and/or persistent threats, and sustained exposure to these stressful events has been argued to result in maladaptive BNST functioning that could underlie anxiety disorders.  Consistent with this hypothesis, previous reports have shown that chronic stress-induced BNST neuroplasticity leads to enhanced excitability within BNST networks to produce heightened anxiety states.  Pituitary adenylate cyclase activating polypeptides (PACAP) have acute neurotransmitter functions in neuronal excitability, long term neurotrophic properties in neuroplasticity, and appear to be key components in stress signaling. In collaboration with Professor Victor May in the Departiment of Anatomy and Neurobiology and Professor Bill Falls and the Falls Laboratory in the Department of Psychology, we are currently determiningthe role of BNST PACAP in mediating stress-induce anxiety-like behavior. Specific questions include:

  • Does chronic stress increase the expression of PACAP and its cognate PAC1 receptor uniquely within the BNST, and is intra-BNST PACAP injection anxiogenic?
  • Does PACAP signaling mediate plasticity within the BNST.

Funded by a grant from UVM's Vice President for Research and Graduate Studies (Research Opportunities Grant Program)

Project 4:  How does the extended amygdala process long- versus short-duration stressful or threatening stimuli?

Based on a number of studies, it seems clear that the BNST mediates fear- and anxiety-like behavior using some behavioral paradigms, whereas the central nucleus of the amygdala (CeA) mediates fear- and anxiety-like behavior in other paradigms.  Based on these data, Michael Davis and colleagues have argued that the BNST mediates long-duration responses to diffuse, chronic, or unpredictable stimuli, whereas the CeA mediates short duration responses when the stimuli are predictable in nature.  Based on this argument, this group has suggested that during exposure to a long-duration threat, axniety-like behavior might initially be mediated by the CeA, but as the duration increased, activity within the circuit would shift from the CeA to the BNST.  Interestingly, Professor Mark Bouton and his group in the Department of Psychology recently showed that the BNST was necessary to observe changes in fear-like behavior when 10-minute predicted footshock, but not when a 1-minute tone predicted the shock, and this group has suggested that during the 10-minute tone, fear-like behavior is initially mediated by the BNST, but as the time of exposure to the 10-minute tone increases (towards the end of the 10 minute tone), activity switches from the BNST to the CeA. Hence, in collaboration with Professor Bouton’s group, we are currently investigating activation within the BNST and CeA following training with 1- and 10-minute tones. 

Project 5: Is the response of neurons in the extended amygdala to serotonin altered during learned helplessness?

In a project funded by the National Alliance for Research on Schizophrenia and Depression (NARSAD), we are investigating the role of 5-HT7 receptors in the BNST in learned helplessness (LH), which is currently poorly understood. We are currently using behavioral, pharmacological and electrophysiological techniques to determine whether changes in BNST 5-HT7 receptors mediate the behavioral changes associated with LH. These studies could lead to a better understanding of the brain mechanisms underlying affective disorders as well as the design of more selective pharmacological treatments for these disorders.

Funded by NARSAD

Publications

  • Hammack, S.E., Cooper, M.A., Lezak, K.R., (in press) Overlapping neurobiology of learned helplessness and conditioned defeat: Implications for PTSD and mood disorders, Neuropharmacology.
  • Ressler, K.J., Mercer, K.B., Bradley, B., Jovanovic, T., Mahan, A., Kerley, K., Norrholm, S.D., Kilaru, V., Smith, A.K., Myers, A.J., Ramirez, M., Engel, A., Hammack., S.E., Toufexis, D., Braas, K.M., Binder, E.B., May, V. (2011) PTSD is associated with the PAC1 receptor and dysregulation of PACAP, Nature, 470: 492-497.
  • Hammack, S.E., Roman, C.W., Lezak, K.R., Kocho-Schellenberg, M., Grimmig, B., Falls, W.A., Braas, K., May, V. (2010) Roles for pituitary adenylate cyclase-activating peptide (PACAP) expression and signaling in the bed nucleus of the stria terminalis (BNST) in mediating the behavioral consequences of chronic stress, Journal of Molecular Neuroscience, in press.
  • Hammack, S.E., Guo, J., Hazra, R., Dabrowska, J., Myers, K.M., Rainnie, D.G. (2009) The response of neurons in the bed nucleus of the stria terminalis to serotonin: Implications for anxiety, Progress in Neuro-Psychopharmacology & Biological Psychiatry, 33(8): 1309-20.
  • Hammack, S.E., Cheung, J., Rhodes, K.M., Schutz, K.C., Falls, W.A., Braas, K.M., May, V. (2009, in press) Chronic stress increases pituitary adenylate cyclase-activating peptide (PACAP) and brain-derived neurotrophic factor (BDNF) mRNA expression in the bed nucleus of the stria terminalis (BNST): roles for PACAP in anxiety-like behavior, Psychoneuroendocrinology.
  • Fox, J.H., Hammack, S.E., Falls, W.A. (2008) Exercise is associated with reduction in the anxiogenic effect of mCPP on acoustic startle, Behavioral Neuroscience 122(4), 943-8.
  • Hammack, S.E., Mania, I., Rainnie, D.G. (2007) Differential expression of intrinsic membrane currents in defined cell types of the anterolateral bed nucleus of the stria terminalis, Journal of Neurophysiology 98(2), 638-56.

Publications via PubMed

Collaborations

UVM

 
William "Bill" Falls Department of Psychology, University of Vermont
Victor May Department of Anatomy and Neurobiology, University of Vermont
Mark Bouton Department of Psychology, University of Vermont
Donna Toufexis Department of Psychology, University of Vermont
John Green Department of Psychology, University of Vermont
   

Emory University

 
Donald "Tig" Rainnie Department of Psychiatry and Center for Behavioral Neuroscience, Emory University
Kerry Ressler Department of Psychiatry and Center for Behavioral Neuroscience, Emory University
Mike Davis Department of Psychiatry and Center for Behavioral Neuroscience, Emory University
   

University of Colorado

 
Steven Maier Department of Psychology and Center for Neuroscience, University of Colorado
Linda Watkins Department of Psychology and Center for Neuroscience, University of Colorado
Christopher Lowry Department of Integrative Physiology and Center for Neuroscience, University of Colorado
Monika Fleshner Department of Integrative Physiology and Center for Neuroscience, University of Colorado
Jerry Rudy Department of Psychology and Center for Neuroscience, University of Colorado
   

Other Institutions

 
Matt Will Department of Psychological Sciences, University of Missouri-Columbia
Terrence Deak Deparment of Psychology, SUNY Binghamton

Resources

electrophysiology

Visually Guided Whole-Cell Patch-Clamp Electrophysiology

  • Molecular Devices Multiclamp 700B Amplifier and accompanying head stages
  • Molecular Devices Digidata 1440A Interface
  • PClamp 10.0 software
  • Leica DM LFSA upright microscope with DIC optics and GFP fluorescence
  • DAGE analog IR camera system
  • TMC 63-531 vibration isolating laboratory table
  • Sutter Instruments MP 285 micromanipulator
  • Dell Optiplex GX620 Computer
  • Siskiyou stage and Recording chamber from Warner Instruments
  • Faraday Cage
  • Heating Supply
  • P-97 Flaming/Brown micropipette puller. 
 
wet lab

Fully Equipped Wet Lab

  • Nissl Staining
  • Immunohistochemistry
  • In Situ Hybridization
  • Leica VT1000s vibrotome
  • Wescor Vapro Osmometer
  • Ohaus Explorer Balance
  • Accumet PH Meter
  • Computers
  • Equipment for stereotaxic surgery and intra-cranial injection of drugs
  • dH2O supply
     
 
 
behavior

Behavioral Testing Rooms

plus maze
Our plus maze
   

Shared Equipment in the Biobehavioral Wing of the Department of Psychology

radial

Radial Arm Maze (Med Associates)

wheels

Rat Running Wheels (Med Associates)

cryostat

Cryostat and Histology Room

stereology

Unbiased Stereology and Image Analysis

surgery

Surgery Suite

Equipment for assessing acoustic startle responding in rodents is also available in the Falls Lab.

In addition, we collaborate with Victor May's laboratory for molecular techniques, including quantitative PCR.

 

 

 

 

 

Last modified July 11 2011 10:24 AM