Adenylyl cyclase-5 in the dorsal striatum function as a molecular switch for the generation of behavioral preferences for cue-directed food choices

Abstract

BackgroundBehavioral choices in habits and innate behaviors occur automatically in the absence of conscious selection. These behaviors are not easily modified by learning. Similar types of behaviors also occur in various mental illnesses including drug addiction, obsessive-compulsive disorder, schizophrenia, and autism. However, underlying mechanisms are not clearly understood. In the present study, we investigated the molecular mechanisms regulating unconditioned preferred behaviors in food-choices.ResultsMice lacking adenylyl cyclase-5 (AC5 KO mice), which is preferentially expressed in the dorsal striatum, consumed food pellets nearly one after another in cages. AC5 KO mice showed aversive behaviors to bitter tasting quinine, but they compulsively chose quinine-containing AC5 KO-pellets over fresh pellets. The unusual food-choice behaviors in AC5 KO mice were due to the gain of behavioral preferences for food pellets containing an olfactory cue, which wild-type mice normally ignored. Such food-choice behaviors in AC5 KO mice disappeared when whiskers were trimmed. Conversely, whisker trimming in wildtype mice induced behavioral preferences for AC5 KO food pellets, indicating that preferred food-choices were not learned through prior experience. Both AC5 KO mice and wildtype mice with trimmed whiskers had increased glutamatergic input from the barrel cortex into the dorsal striatum, resulting in an increase in the mGluR1-dependent signaling cascade. The siRNA-mediated inhibition of mGluR1 in the dorsal striatum in AC5 KO mice and wildtype mice with trimmed whiskers abolished preferred choices for AC5 KO food pellets, whereas siRNA-mediated inhibition of mGluR3 glutamate receptors in the dorsal striatum in wildtype mice induced behavioral preferences for AC5 KO food pellets, thus mimicking AC5 KO phenotypes.ConclusionsOur results show that the gain and loss of behavioral preferences for a specific cue-directed option were regulated by specific cellular factors in the dorsal striatum, such that the preferred food choices were switched on when either the mGluR3-AC5 pathway was inactive or the mGluR1 pathway was active, whereas the preferred food-choices were switched off when mGluR1 or its downstream pathway was suppressed. These results identify the AC5 and mGluR system in the dorsal striatum as molecular on/off switches to direct decisions on behavioral preferences for cue-oriented options.

Functional Connectivity of Basolateral Amygdala Neurons Carrying Orexin Receptors and Melanin-concentrating Hormone Receptors in Regulating Sociability and Mood-related Behaviors

“…Next, we attempted to visualize the brain regions that were innervated by BLA neurons using the viral vector system AAV2-CaMKII-ChR2-eYFP, which allowed us to label axonal projections of infected neurons due to the expression of eYFP, as demonstrated previously [24]. Eighteen days after the stereotaxic injection of AAV2-CaMKII-ChR2-eYFP into the BLA, mice were sacrificed and axonal tracts of BLA neurons labeled by eYFP were analyzed in brain sections (Fig.…”

“…Stereotaxic injection of AAV2-CaMKII-ChR2-eYFP was performed as described previously [24]. Adeno-associated virus (AAV) carrying the channel rhodopsin-2-eYFP fusion gene driven by the CaMKII promoter was purchased from the University of Pennsylvania Vector Core (AV-1-26969P, 1.15×10 13 viral particles/ml; UPenn, Philadelphia, PA, USA).…”

Behavioral appraisal by implementing a short sequence of stress resolves adaptively changed stress gains

“…Cannula implantation and drug infusion were performed as described previously 63 . In brief, mice were anesthetized with ketamine and xylazine (3.5: 1).…”

“…Fluorescence images were collected and analyzed using an Olympus BX 51 microscope equipped with an X-cite 120 uorescence illuminator (EXFO Life Science & Industrial Division, Ontario, Canada), a DP71 camera (Olympus), and MetaMorph Microscopy Automation & Image Analysis software (Molecular Devices, Sunnyvale, CA, USA). Microinjection of small-interfering RNA (siRNA)Stereotaxic injection of siRNA was carried out as described previously38,63 . Brie y, mice were anesthetized with a mixture of ketamine hydrochloride (50 mg/ml) and xylazine hydrochloride (23.3 mg /ml) (3.5: 1) at a dose of 2.5 ml/g body weight.…”

Reversal of an Unconditioned Behavioral Preference for Specific Food Pellets by Intervention of Whisker Sensory Inputs

“…AC5 KO mice exhibit a behavioral preference for food pellets containing an olfactory cue produced by AC5 KO mice (AC5 KO pellets) over food pellets containing an olfactory cue produced by WT mice (WT pellets). Interestingly, bilateral whisker trimming in AC5 KO mice blocks the expression of this behavioral preference for AC5 KO pellets, while such whisker trimming in WT mice induces this behavioral preference [ 7 ]. These results suggest that AC5 KO mice can be used as an animal model to study possible modulation of unconditioned behavioral preferences in relation to the neural activity of sensory inputs.…”