mGlu₁ and mGlu₅ modulate distinct excitatory inputs to the nucleus accumbens shell

Area of Science:

• Neuroscience
• Synaptic Plasticity
• Receptor Pharmacology

Background:

• Glutamatergic transmission in the nucleus accumbens shell (NAcSh) underlies reward learning and motivation.
• Metabotropic glutamate (mGlu) receptors modulate NAcSh synaptic strength via long-term depression (LTD).
• Distinct neural pathways (prefrontal cortex [PFC] and medio-dorsal thalamus [MDT]) influence motivated behaviors, but their mGlu receptor regulation is unknown.

Purpose of the Study:

• To investigate Group I mGlu receptor regulation of PFC and MDT glutamatergic synapses onto specific NAc medium spiny neuron (MSN) populations.
• To explore how cocaine exposure alters mGlu receptor-mediated plasticity at these synapses.

Main Methods:

• Utilized D1tdTom BAC transgenic mice and optogenetics to study synaptic plasticity.
• Examined synaptically evoked LTD at MDT-NAcSh and PFC-NAcSh synapses.
• Assessed the effects of chronic cocaine exposure and an mGlu5-positive allosteric modulator (PAM) on LTD.

Main Results:

• MDT-NAcSh LTD required mGlu5 and was specific to D1(+) MSNs.
• PFC-induced LTD involved mGlu1 and occurred in both D1(+) and D1(-) MSNs.
• Cocaine exposure attenuated MDT-D1(+) synapse LTD, which was rescued by an mGlu5 PAM (VU0409551).

Conclusions:

• Group I mGlu receptors exhibit distinct roles in regulating plasticity at PFC and MDT synapses within the NAcSh.
• These findings reveal unique synaptic plasticity mechanisms governing specific NAcSh circuits.
• The study identifies potential therapeutic targets for reversing cocaine-induced synaptic deficits.