title: Food-associated cues alter forebrain functional connectivity as assessed with immediate early gene and proenkephalin expression.
abstract: BACKGROUND
  Cues predictive of food availability are powerful modulators of appetite as well as food-seeking and ingestive behaviors. The neurobiological underpinnings of these conditioned responses are not well understood. Monitoring regional immediate early gene expression is a method used to assess alterations in neuronal metabolism resulting from upstream intracellular and extracellular signaling. Furthermore, assessing the expression of multiple immediate early genes offers a window onto the possible sequelae of exposure to food cues, since the function of each gene differs. We used immediate early gene and proenkephalin expression as a means of assessing food cue-elicited regional activation and alterations in functional connectivity within the forebrain.
  
  
  RESULTS
  Contextual cues associated with palatable food elicited conditioned motor activation and corticosterone release in rats. This motivational state was associated with increased transcription of the activity-regulated genes homer1a, arc, zif268, ngfi-b and c-fos in corticolimbic, thalamic and hypothalamic areas and of proenkephalin within striatal regions. Furthermore, the functional connectivity elicited by food cues, as assessed by an inter-regional multigene-expression correlation method, differed substantially from that elicited by neutral cues. Specifically, food cues increased cortical engagement of the striatum, and within the nucleus accumbens, shifted correlations away from the shell towards the core. Exposure to the food-associated context also induced correlated gene expression between corticostriatal networks and the basolateral amygdala, an area critical for learning and responding to the incentive value of sensory stimuli. This increased corticostriatal-amygdalar functional connectivity was absent in the control group exposed to innocuous cues.
  
  
  CONCLUSIONS
  The results implicate correlated activity between the cortex and the striatum, especially the nucleus accumbens core and the basolateral amygdala, in the generation of a conditioned motivated state that may promote excessive food intake. The upregulation of a number of genes in unique patterns within corticostriatal, thalamic, and hypothalamic networks suggests that food cues are capable of powerfully altering neuronal processing in areas mediating the integration of emotion, cognition, arousal, and the regulation of energy balance. As many of these genes play a role in plasticity, their upregulation within these circuits may also indicate the neuroanatomic and transcriptional correlates of extinction learning.
authors.affiliation: Medical Scientist and Neuroscience Training Programs, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI 53705, USA. cschiltz@wisc.edu
authors.forename: Craig A
authors.initials: CA
authors.lastname: Schiltz
authors.forename: Quentin Z
authors.initials: QZ
authors.lastname: Bremer
authors.forename: Charles F
authors.initials: CF
authors.lastname: Landry
authors.forename: Ann E
authors.initials: AE
authors.lastname: Kelley
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D003463:Cues; D004745:Enkephalins / Q000096:biosynthesis* / Q000235:genetics; D005247:Feeding Behavior / Q000502:physiology*; D005502:Food; D005786:Gene Expression Regulation / Q000502:physiology; D017781:Genes, Immediate-Early / Q000502:physiology*; D007858:Learning / Q000502:physiology; D008297:Male; D009415:Nerve Net / Q000378:metabolism*; D016548:Prosencephalon / Q000378:metabolism*; D011498:Protein Precursors / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004745:Enkephalins; D011498:Protein Precursors; D012333:RNA, Messenger; C029992:proenkephalin