Role of dopamine neurons in familiarity.

Dopamine neurons signal the salience of environmental stimuli and influence learning, although it is less clear if these neurons also determine the salience of memories. Ventral tegmental area (VTA) dopamine neurons increase their firing in the presence of new objects and reduce it upon repeated, inconsequential exposures, marking the shift from novelty to familiarity. This study investigates how dopamine neuron activity during repeated familiar object exposure affects an animal's preference for new objects in a subsequent novel object recognition (NOR) test. We hypothesize that a single familiarization session will not sufficiently lower dopamine activity, such that the memory of a familiar object remains salient, leading to equal exploration of familiar and novel objects and weaker NOR discrimination. In contrast, multiple familiarization sessions likely suppress dopamine activity more effectively, reducing the salience of the familiar object and enhancing subsequent novelty discrimination. Our experiments in mice indicated that multiple familiarization sessions reduce VTA dopamine neuron activation, as measured by c-Fos expression, and enhance novelty discrimination compared with a single familiarization session. Dopamine neurons that show responsiveness to novelty were primarily located in the paranigral nucleus of the VTA and expressed vesicular glutamate transporter 2 transcripts, marking them as dopamine-glutamate neurons. Chemogenetic inhibition of dopamine neurons during a single session paralleled the effects of multiple sessions, improving NOR. These findings suggest that a critical role of dopamine neurons during the transition from novelty to familiarity is to modulate the salience of an object's memory.

Role of Dopamine Neurons in Familiarity.

Dopamine neurons signal the salience of environmental stimuli, influencing learning and motivation. However, research has not yet identified whether dopamine neurons also modulate the salience of memory content. Dopamine neuron activity in the ventral tegmental area (VTA) increases in response to novel objects and diminishes as objects become familiar through repeated presentations. We proposed that the declined rate of dopamine neuron activity during familiarization affects the salience of a familiar object's memory. This, in turn, influences the degree to which an animal distinguishes between familiar and novel objects in a subsequent novel object recognition (NOR) test. As such, a single familiarization session may not sufficiently reduce dopamine activity, allowing the memory of a familiar object to maintain its salience and potentially attenuating NOR. In contrast, multiple familiarization sessions could lead to more pronounced dopamine activity suppression, strengthening NOR. Our data in mice reveals that, compared to a single session, multiple sessions result in decreased VTA dopamine neuron activation, as indicated by c-Fos measurements, and enhanced novelty discrimination. Critically, when VTA dopamine neurons are chemogenetically inhibited during a single familiarization session, NOR improves, mirroring the effects of multiple familiarization sessions. In summary, our findings highlight the pivotal function of dopamine neurons in familiarity and suggest a role in modulating the salience of memory content.

Single Dose of Amphetamine Induces Delayed Subregional Attenuation of Cholinergic Interneuron Activity in the Striatum.

Psychostimulants such as amphetamine (AMPH) target dopamine (DA) neuron synapses to engender drug-induced plasticity. While DA neurons modulate the activity of striatal (Str) cholinergic interneurons (ChIs) with regional heterogeneity, how AMPH affects ChI activity has not been elucidated. Here, we applied quantitative fluorescence imaging approaches to map the dose-dependent effects of a single dose of AMPH on ChI activity at 2.5 and 24 h after injection across the mouse Str using the activity-dependent marker phosphorylated ribosomal protein S6 (p-rpS6240/244). AMPH did not affect the distribution or morphology of ChIs in any Str subregion. While AMPH at either dose had no effect on ChI activity after 2.5 h, ChI activity was dose dependently reduced after 24 h specifically in the ventral Str/nucleus accumbens (NAc), a critical site of psychostimulant action. AMPH at either dose did not affect the spontaneous firing of ChIs. Altogether this work demonstrates that a single dose of AMPH has delayed regionally heterogeneous effects on ChI activity, which most likely involves extra-Str synaptic input.