Fear induced neuronal alterations in a genetic model of depression: An fMRI study on awake animals

Previous human imaging studies used facial stimuli to explore the potential association between depression and fear. This study aimed at investigating brain alterations in a rodent model of depression when innate fear was induced in the form of the predator odor trimethylthiazoline (TMT). Flinders sensitive line (FSL) rats, a genetic animal model of depression, and their control counterpart Flinders resistant line (FRL), were used in this functional magnetic resonance imaging (fMRI) assessment. Compared to FRL, FSL rats exhibited greater BOLD activation in the cortical amygdala and hypoactivation in the prefrontal cortex in response to TMT, suggesting cortico-amygdalar dysfunction in the depressed strain. In addition, the hyperactivation in the insular cortex in FSL rats may be the basis for enhanced neuronal responses to fear and aversion in depression. These results are evidence for the value of translational models of depression in expanding understanding of the neural circuitries sub-serving common human co-morbidities like depression and fear.

[1]  P. Boesiger,et al.  Imbalance between Left and Right Dorsolateral Prefrontal Cortex in Major Depression Is Linked to Negative Emotional Judgment: An fMRI Study in Severe Major Depressive Disorder , 2008, Biological Psychiatry.

[2]  R. Neve,et al.  Effects of cyclic adenosine monophosphate response element binding protein overexpression in the basolateral amygdala on behavioral models of depression and anxiety , 2004, Biological Psychiatry.

[3]  Larry W. Swanson,et al.  Brain Maps: Structure of the Rat Brain , 1992 .

[4]  A. Zangen,et al.  Limbic dopaminergic adaptation to a stressful stimulus in a rat model of depression , 2001, Brain Research.

[5]  Gregor Thut,et al.  Effect of low-frequency transcranial magnetic stimulation on an affective go/no-go task in patients with major depression: Role of stimulation site and depression severity , 2006, Psychiatry Research.

[6]  J. King,et al.  Female fear: Influence of estrus cycle on behavioral response and neuronal activation , 2009, Behavioural Brain Research.

[7]  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.

[8]  Michael Davis,et al.  Olfactory bulbectomy enhances sensitization of the acoustic startle reflex produced by acute or repeated stress. , 1997, Behavioral neuroscience.

[9]  A. Carobrez,et al.  Olfactory fear conditioning paradigm in rats: Effects of midazolam, propranolol or scopolamine , 2009, Neurobiology of Learning and Memory.

[10]  J. Rosen,et al.  Analysis of behavioral constraints and the neuroanatomy of fear to the predator odor trimethylthiazoline: A model for animal phobias , 2008, Neuroscience & Biobehavioral Reviews.

[11]  Irene Tracey,et al.  The influence of negative emotions on pain: Behavioral effects and neural mechanisms , 2009, NeuroImage.

[12]  J. Lagopoulos,et al.  Is a lack of disgust something to fear? A functional magnetic resonance imaging facial emotion recognition study in euthymic bipolar disorder patients. , 2007, Bipolar disorders.

[13]  K. Fuxe,et al.  Alterations in neuropeptide Y levels and Y1 binding sites in the Flinders Sensitive Line rats, a genetic animal model of depression , 1999, Neuroscience Letters.

[14]  R. Roth,et al.  The predator odor, TMT, displays a unique, stress-like pattern of dopaminergic and endocrinological activation in the rat , 2000, Brain Research.

[15]  O. Puciłowski,et al.  Effect of verapamil on submissive behavior in genetically bred hypercholinergic rats in a water competition test. , 1990, European journal of pharmacology.

[16]  Karl J. Friston,et al.  Brain Systems Mediating Aversive Conditioning: an Event-Related fMRI Study , 1998, Neuron.

[17]  Olga V. Demler,et al.  The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). , 2003, JAMA.

[18]  M. Fendt,et al.  Temporary Inactivation of the Bed Nucleus of the Stria Terminalis But Not of the Amygdala Blocks Freezing Induced by Trimethylthiazoline, a Component of Fox Feces , 2003, The Journal of Neuroscience.

[19]  D. Overstreet,et al.  The brain 5‐HT4 receptor binding is down‐regulated in the Flinders Sensitive Line depression model and in response to paroxetine administration , 2009, Journal of neurochemistry.

[20]  R. Russell,et al.  Selective breeding for sensitivity to the anticholinesterase DFP , 1979, Psychopharmacology.

[21]  M. Thase,et al.  Increased Amygdala and Decreased Dorsolateral Prefrontal BOLD Responses in Unipolar Depression: Related and Independent Features , 2007, Biological Psychiatry.

[22]  Wei Chen,et al.  Imaging unconditioned fear response with manganese-enhanced MRI (MEMRI) , 2007, NeuroImage.

[23]  D. Overstreet,et al.  The flinders sensitive line rats: A genetic animal model of depression , 1993, Neuroscience & Biobehavioral Reviews.

[24]  Deanna M Barch,et al.  Antidepressant treatment normalizes hypoactivity in dorsolateral prefrontal cortex during emotional interference processing in major depression. , 2009, Journal of affective disorders.

[25]  Karl J. Friston,et al.  Movement‐Related effects in fMRI time‐series , 1996, Magnetic resonance in medicine.

[26]  P. Cowen,et al.  Increased neural response to fear in patients recovered from depression: a 3T functional magnetic resonance imaging study , 2009, Psychological Medicine.

[27]  K. Davis,et al.  Two systems of resting state connectivity between the insula and cingulate cortex , 2009, Human brain mapping.

[28]  A. Simmons,et al.  Right Anterior Insula Hypoactivity During Anticipation of Homeostatic Shifts in Major Depressive Disorder , 2010, Psychosomatic medicine.

[29]  E. Frank,et al.  Impaired extinction of learned fear in rats selectively bred for high anxiety – evidence of altered neuronal processing in prefrontal-amygdala pathways , 2008, The European journal of neuroscience.

[30]  J. Strupp Stimulate: A GUI based fMRI analysis software package , 1996, NeuroImage.

[31]  D. Overstreet,et al.  Cholinergic/Serotonergic Interactions in Hypothermia: Implications for Rat Models of Depression , 1998, Pharmacology Biochemistry and Behavior.

[32]  E. Frank,et al.  Genetic predisposition to anxiety-related behavior determines coping style, neuroendocrine responses, and neuronal activation during social defeat. , 2006, Behavioral neuroscience.

[33]  D. Overstreet Commentary: A behavioral, psychopharmacological, and neurochemical update on the flinders sensitive line rat, a potential genetic animal model of depression , 1991, Behavior genetics.

[34]  M. Diksic,et al.  A genetic rat model of depression, Flinders sensitive line, has a lower density of 5-HT1A receptors, but a higher density of 5-HT1B receptors, compared to control rats , 2009, Neurochemistry International.

[35]  Binbin Nie,et al.  Cerebral and cerebellar gray matter reduction in first-episode patients with major depressive disorder: a voxel-based morphometry study. , 2011, European journal of radiology.

[36]  Hackjin Kim,et al.  Functional neuroimaging studies of the amygdala in depression. , 2002, Seminars in clinical neuropsychiatry.

[37]  C. Ferris,et al.  Imaging brain activity in conscious animals using functional MRI , 1998, Journal of Neuroscience Methods.

[38]  J. Seok,et al.  Neural correlates of affective processing in response to sad and angry facial stimuli in patients with major depressive disorder , 2008, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[39]  J. Rosen,et al.  The neurobiology of conditioned and unconditioned fear: a neurobehavioral system analysis of the amygdala. , 2004, Behavioral and cognitive neuroscience reviews.

[40]  A. Mathé,et al.  Increased levels of cocaine and amphetamine regulated transcript in two animal models of depression and anxiety , 2009, Neurobiology of Disease.

[41]  D. Overstreet,et al.  Impaired active avoidance responding in rats selectively bred for increased cholinergic function , 1990, Physiology & Behavior.

[42]  M. Mintun,et al.  Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study , 2001, Biological Psychiatry.

[43]  Joseph E LeDoux Fear and the brain: where have we been, and where are we going? , 1998, Biological Psychiatry.

[44]  Wei Chen,et al.  Procedure for minimizing stress for fMRI studies in conscious rats , 2005, Journal of Neuroscience Methods.

[45]  D. Overstreet,et al.  Natural and Cellular Immune Responses in Flinders Sensitive and Resistant Line Rats , 1996, Neuropsychopharmacology.

[46]  D. Overstreet,et al.  Ontogeny of Muscarinic Cholinergic Supersensitivity in the Flinders Sensitive Line Rat , 1999, Pharmacology Biochemistry and Behavior.

[47]  H. Anisman,et al.  Altered metabolic and neurochemical responses to chronic unpredictable stressors in ghrelin receptor‐deficient mice , 2010, The European journal of neuroscience.

[48]  R. Kessler,et al.  Comorbidity of DSM–III–R Major Depressive Disorder in the General Population: Results from the US National Comorbidity Survey , 1996, British Journal of Psychiatry.

[49]  D. Overstreet,et al.  Free-running period of circadian rhythms is shorter in rats with a genetically upregulated central cholinergic system , 1994, Biological Psychiatry.

[50]  A. Ylinen,et al.  Reciprocal Connections between the Amygdala and the Hippocampal Formation, Perirhinal Cortex, and Postrhinal Cortex in Rat: A Review , 2000, Annals of the New York Academy of Sciences.

[51]  K. Luan Phan,et al.  Functional Neuroanatomy of Emotion: A Meta-Analysis of Emotion Activation Studies in PET and fMRI , 2002, NeuroImage.

[52]  J. Rosen,et al.  Predator odor as an unconditioned fear stimulus in rats: elicitation of freezing by trimethylthiazoline, a component of fox feces. , 2000, Behavioral neuroscience.

[53]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[54]  R. Dielenberg,et al.  Defensive behavior in rats towards predatory odors: a review , 2001, Neuroscience & Biobehavioral Reviews.

[55]  K P Ossenkopp,et al.  Brief predator odour exposure activates the HPA axis independent of locomotor changes. , 1999, Neuroreport.

[56]  Abraham Z. Snyder,et al.  Altered Emotional Interference Processing in Affective and Cognitive-Control Brain Circuitry in Major Depression , 2008, Biological Psychiatry.

[57]  D. Overstreet,et al.  The Flinders Sensitive Line rat: A selectively bred putative animal model of depression , 2005, Neuroscience & Biobehavioral Reviews.

[58]  F. Bloom,et al.  Psychopharmacology: The Fourth Generation of Progress , 1995 .

[59]  N. Canteras,et al.  New Perspectives on β-Adrenergic Mediation of Innate and Learned Fear Responses to Predator Odor , 2008, The Journal of Neuroscience.

[60]  J. Tinsley Oden,et al.  Fifth US National Congress on Computational Mechanics , 1999 .