Submitted by Rhonda Kolaric (Biology)
Abstract: It is well established that dopamine (DA) neurons in the ventral midbrain signal novelty by increasing their bursting activity, while decreasing it after repeated inconsequential stimulus presentations. Thus, the lack of DA neuron burst activity is a physiological signature that a particular stimulus has become familiar. We hypothesized that decreasing DA neuron activity while animals explore objects for the first time enhances familiarization and improves subsequent novel object discrimination.
We showed that novel object recognition (NOR) depends on the amount of pre-exposure to the familiar object, such that two familiarization sessions over two days produce robust novelty discrimination, while one familiarization session does not produce novelty discrimination during the NOR task. This lack of NOR reflects a stage of equal attention allocated to both stimuli, could be interpreted as a weakened memory of the previously seen familiar stimulus.
To investigate whether decreasing DA neuron activity increases familiarity and prompts gain-of-function in NOR, we chemogenetically inhibited DA neurons in the ventral tegmental area (VTA) during the familiarization session of NOR paradigm that results in poor novelty discrimination. We injected an AAV flp-dependent hM4D into the VTA of TH-flp transgenic mice to selectively inhibit TH-positive DA neurons. The virus was activated via injection of Clozapine N-oxide dihydrochloride (i.p.) 30 minutes before trial. We found that inhibiting DA neurons during the familiarization phase resulted in enhanced novelty discrimination in experimental animals compared to controls, while inhibiting DA neurons after familiarization does not, suggesting that suppressing DA activity ameliorates novelty discrimination by enhancing familiarity.
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