Alterations in Prefrontal-Limbic Functional Activation and Connectivity in Chronic Stress-Induced Visceral Hyperalgesia

Repeated water avoidance stress (WAS) induces sustained visceral hyperalgesia (VH) in rats measured as enhanced visceromotor response to colorectal distension (CRD). This model incorporates two characteristic features of human irritable bowel syndrome (IBS), VH and a prominent role of stress in the onset and exacerbation of IBS symptoms. Little is known regarding central mechanisms underlying the stress-induced VH. Here, we applied an autoradiographic perfusion method to map regional and network-level neural correlates of VH. Adult male rats were exposed to WAS or sham treatment for 1 hour/day for 10 days. The visceromotor response was measured before and after the treatment. Cerebral blood flow (CBF) mapping was performed by intravenous injection of radiotracer ([14C]-iodoantipyrine) while the rat was receiving a 60-mmHg CRD or no distension. Regional CBF-related tissue radioactivity was quantified in autoradiographic images of brain slices and analyzed in 3-dimensionally reconstructed brains with statistical parametric mapping. Compared to sham rats, stressed rats showed VH in association with greater CRD-evoked activation in the insular cortex, amygdala, and hypothalamus, but reduced activation in the prelimbic area (PrL) of prefrontal cortex. We constrained results of seed correlation analysis by known structural connectivity of the PrL to generate structurally linked functional connectivity (SLFC) of the PrL. Dramatic differences in the SLFC of PrL were noted between stressed and sham rats under distension. In particular, sham rats showed negative correlation between the PrL and amygdala, which was absent in stressed rats. The altered pattern of functional brain activation is in general agreement with that observed in IBS patients in human brain imaging studies, providing further support for the face and construct validity of the WAS model for IBS. The absence of prefrontal cortex-amygdala anticorrelation in stressed rats is consistent with the notion that impaired corticolimbic modulation acts as a central mechanism underlying stress-induced VH.

[1]  Michael Davis,et al.  Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. , 2003, European journal of pharmacology.

[2]  J. Feldon,et al.  Effect of social isolation on stress-related behavioural and neuroendocrine state in the rat , 2004, Behavioural Brain Research.

[3]  S. Kapur,et al.  Direct Activation of the Ventral Striatum in Anticipation of Aversive Stimuli , 2003, Neuron.

[4]  D. Myers,et al.  Stereotaxic delivery of corticosterone to the amygdala modulates colonic sensitivity in rats , 2001, Brain Research.

[5]  G. Gerken,et al.  Psychological stress and the severity of post‐inflammatory visceral hyperalgesia , 2007, European journal of pain.

[6]  Y. Taché,et al.  Proximal colon distension induces Fos expression in the brain and inhibits gastric emptying through capsaicin-sensitive pathways in conscious rats , 2006, Brain Research.

[7]  G. Quirk,et al.  The Role of Ventromedial Prefrontal Cortex in the Recovery of Extinguished Fear , 2000, The Journal of Neuroscience.

[8]  H. Fields,et al.  Pain modulation: expectation, opioid analgesia and virtual pain. , 2000, Progress in brain research.

[9]  S. Chattarji,et al.  Effects of chronic stress on dendritic arborization in the central and extended amygdala , 2003, Brain Research.

[10]  E. Mayer,et al.  Regional brain activation in conscious, nonrestrained rats in response to noxious visceral stimulation , 2008, PAIN.

[11]  B. Mensour,et al.  Neural circuitry underlying voluntary suppression of sadness , 2003, Biological Psychiatry.

[12]  Y. Taché,et al.  Stress and visceral pain: From animal models to clinical therapies , 2012, Experimental Neurology.

[13]  G. Boeckxstaens,et al.  Altered brain activation to colorectal distention in visceral hypersensitive maternal‐separated rats , 2012, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[14]  Doris Y. Tsao,et al.  Functional Connectivity in the Brain: Effects of Anesthesia , 2011, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[15]  G. Paxinos.  The Rat nervous system , 1985 .

[16]  J. Herbert,et al.  c-fos expression, behavioural, endocrine and autonomic responses to acute social stress in male rats after chronic restraint: modulation by serotonin , 1999, Neuroscience.

[17]  Olaf Sporns,et al.  The Human Connectome: A Structural Description of the Human Brain , 2005, PLoS Comput. Biol..

[18]  Emeran A. Mayer,et al.  Functional brain activation during retrieval of visceral pain-conditioned passive avoidance in the rat , 2011, PAIN.

[19]  G. Holstege,et al.  The emotional motor system. , 1992, European journal of morphology.

[20]  E. Mayer,et al.  Studying the Brain–Gut Axis with Pharmacological Imaging , 2008, Annals of the New York Academy of Sciences.

[21]  Susan C. Cook,et al.  Chronic stress alters dendritic morphology in rat medial prefrontal cortex. , 2004, Journal of neurobiology.

[22]  K. Phan,et al.  Neural substrates for voluntary suppression of negative affect: A functional magnetic resonance imaging study , 2005, Biological Psychiatry.

[23]  Lin Chang.  The role of stress on physiologic responses and clinical symptoms in irritable bowel syndrome. , 2011, Gastroenterology.

[24]  I. Tracey,et al.  Brain imaging approaches to the study of functional GI disorders: A Rome Working Team Report , 2009, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[25]  Christian Grillon,et al.  The adaptive threat bias in anxiety: Amygdala–dorsomedial prefrontal cortex coupling and aversive amplification , 2012, NeuroImage.

[26]  T. Dinan,et al.  Chronic psychosocial stress induces visceral hyperalgesia in mice , 2012, Stress.

[27]  Larry W. Swanson,et al.  Brain architecture management system , 2007, Neuroinformatics.

[28]  M. Boly,et al.  Influence of anesthesia on cerebral blood flow, cerebral metabolic rate, and brain functional connectivity , 2011, Current opinion in anaesthesiology.

[29]  Jennifer S. Labus,et al.  Sex differences in functional brain activation during noxious visceral stimulation in rats , 2009, PAIN®.

[30]  Raymond J. Dolan,et al.  Anxiety Reduction through Detachment: Subjective, Physiological, and Neural Effects , 2005, Journal of Cognitive Neuroscience.

[31]  E. Mayer,et al.  The brain-gut axis in abdominal pain syndromes. , 2011, Annual review of medicine.

[32]  S. Derbyshire,et al.  Cerebral Activation in Patients With Irritable Bowel Syndrome and Control Subjects During Rectosigmoid Stimulation , 2001, Psychosomatic medicine.

[33]  D. Paré,et al.  Stimulation of Medial Prefrontal Cortex Decreases the Responsiveness of Central Amygdala Output Neurons , 2003, The Journal of Neuroscience.

[34]  L. Jasmin,et al.  Rostral agranular insular cortex and pain areas of the central nervous system: A tract‐tracing study in the rat , 2004, The Journal of comparative neurology.

[35]  A. Craig,et al.  REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY Neuroimaging of the Brain-Gut Axis: From Basic Understanding to Treatment of Functional GI Disorders , 2006 .

[36]  J. Cryan,et al.  Colorectal distension-induced prefrontal cortex activation in the Wistar–Kyoto rat: implications for irritable bowel syndrome , 2010, Neuroscience.

[37]  Kirsten Tillisch,et al.  Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndrome. , 2011, Gastroenterology.

[38]  Kevin N. Ochsner,et al.  For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion , 2004, NeuroImage.

[39]  J. Morrison,et al.  Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex , 2004, Neuroscience.

[40]  Karl J. Friston.  Functional and Effective Connectivity: A Review , 2011, Brain Connect..

[41]  Howard C. Tenenbaum,et al.  Abnormal cortical activity in patients with temporomandibular disorder evoked by cognitive and emotional tasks , 2011, PAIN®.

[42]  S. Chattarji,et al.  Chronic Stress Induces Contrasting Patterns of Dendritic Remodeling in Hippocampal and Amygdaloid Neurons , 2002, The Journal of Neuroscience.

[43]  T. Preuss.  Do Rats Have Prefrontal Cortex? The Rose-Woolsey-Akert Program Reconsidered , 1995, Journal of Cognitive Neuroscience.

[44]  O. Scremin,et al.  An implantable bolus infusion pump for use in freely moving, nontethered rats. , 2002, American journal of physiology. Heart and circulatory physiology.

[45]  Jun Yang,et al.  Statistical parametric mapping applied to an autoradiographic study of cerebral activation during treadmill walking in rats , 2004, NeuroImage.

[46]  O Sporns,et al.  Predicting human resting-state functional connectivity from structural connectivity , 2009, Proceedings of the National Academy of Sciences.

[47]  L. Akkermans,et al.  Long-lasting changes in central nervous system responsivity to colonic distention after stress in rats. , 2002, Gastroenterology.

[48]  M. Fanselow,et al.  Repeated exposure to water avoidance stress in rats: a new model for sustained visceral hyperalgesia. , 2005, American journal of physiology. Gastrointestinal and liver physiology.

[49]  Larry W. Swanson,et al.  Combining collation and annotation efforts toward completion of the rat and mouse connectomes in BAMS , 2012, Front. Neuroinform..

[50]  Leah Fitzgerald,et al.  Condition-specific deactivation of brain regions by 5-HT3 receptor antagonist Alosetron. , 2002, Gastroenterology.

[51]  G. Borszcz.  Contribution of the ventromedial hypothalamus to generation of the affective dimension of pain , 2006, Pain.

[52]  G. Dantas,et al.  Long-lasting delayed hyperalgesia after chronic restraint stress in rats—effect of morphine administration , 2003, Neuroscience Research.

[53]  H. Breiter,et al.  Reward Circuitry Activation by Noxious Thermal Stimuli , 2001, Neuron.

[54]  B. Kolb,et al.  Do rats have a prefrontal cortex? , 2003, Behavioural Brain Research.

[55]  B. Myers,et al.  Differential involvement of amygdala corticosteroid receptors in visceral hyperalgesia following acute or repeated stress. , 2012, American journal of physiology. Gastrointestinal and liver physiology.

[56]  Alberto Granato,et al.  Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex , 2003, Nature.

[57]  R. Depoortère,et al.  Chronic restraint stress induces mechanical and cold allodynia, and enhances inflammatory pain in rat: Relevance to human stress-associated painful pathologies , 2009, Behavioural Brain Research.

[58]  M. Beauregard,et al.  Neural Correlates of Conscious Self-Regulation of Emotion , 2001, The Journal of Neuroscience.

[59]  Richard J. Davidson,et al.  Amygdala–prefrontal coupling underlies individual differences in emotion regulation , 2012, NeuroImage.

[60]  Hao Sun,et al.  Cognitive Impairment in Pain through Amygdala-Driven Prefrontal Cortical Deactivation , 2010, The Journal of Neuroscience.

[61]  V. Neugebauer,et al.  Differential sensitization of amygdala neurons to afferent inputs in a model of arthritic pain. , 2003, Journal of neurophysiology.

[62]  M. Dallman,et al.  Neuroanatomical basis for facilitation of hypothalamic-pituitary-adrenal responses to a novel stressor after chronic stress , 1998, Neuroscience.

[63]  P. Plotsky,et al.  Neonatal maternal separation alters stress-induced responses to viscerosomatic nociceptive stimuli in rat. , 2002, American journal of physiology. Gastrointestinal and liver physiology.

[64]  F. Vives,et al.  Electrophysiological study of the response of medial prefrontal cortex neurons to stimulation of the basolateral nucleus of the amygdala in the rat , 1991, Brain Research.

[65]  Brent A. Vogt,et al.  CHAPTER 22 – Cingulate Cortex and Disease Models , 2004 .

[66]  J. Price,et al.  Prefrontal cortical projections to longitudinal columns in the midbrain periaqueductal gray in Macaque monkeys , 1998, The Journal of comparative neurology.

[67]  Robert P. Vertes,et al.  Interactions among the medial prefrontal cortex, hippocampus and midline thalamus in emotional and cognitive processing in the rat , 2006, Neuroscience.

[68]  A. Grace,et al.  Chronic Cold Stress Alters Prefrontal Cortical Modulation of Amygdala Neuronal Activity in Rats , 2005, Biological Psychiatry.

[69]  Katiuscia Sacco,et al.  Functional connectivity of the insula in the resting brain , 2011, NeuroImage.

[70]  A. McIntosh,et al.  Structural modeling of functional neural pathways mapped with 2-deoxyglucose: effects of acoustic startle habituation on the auditory system , 1991, Brain Research.

[71]  B. Lumb,et al.  Visceral inputs to neurons in the anterior hypothalamus including those that project to the periaqueductal gray: a functional anatomical and electrophysiological study , 2000, Neuroscience.

[72]  P. Sawchenko,et al.  A Common Substrate for Prefrontal and Hippocampal Inhibition of the Neuroendocrine Stress Response , 2011, The Journal of Neuroscience.

[73]  G. Nappi,et al.  Effects of acute and chronic restraint stress on nitroglycerin-induced hyperalgesia in rats , 2005, Neuroscience Letters.

[74]  J. Rosenkranz,et al.  Chronic Stress Causes Amygdala Hyperexcitability in Rodents , 2010, Biological Psychiatry.

[75]  Michel Baudry,et al.  The amygdala modulates prefrontal cortex activity relative to conditioned fear , 1999, Nature.

[76]  Niels Birbaumer,et al.  Disrupted Functional Connectivity of the Pain Network in Fibromyalgia , 2012, Psychosomatic medicine.

[77]  C. Liston,et al.  Psychosocial stress reversibly disrupts prefrontal processing and attentional control , 2009, Proceedings of the National Academy of Sciences.

[78]  Bruce S. McEwen,et al.  Stress-Induced Alterations in Prefrontal Cortical Dendritic Morphology Predict Selective Impairments in Perceptual Attentional Set-Shifting , 2006, The Journal of Neuroscience.

[79]  H. Groenewegen,et al.  The nucleus accumbens: gateway for limbic structures to reach the motor system? , 1996, Progress in brain research.

[80]  C. Wellman,et al.  Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. , 2001, Journal of neurobiology.