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Synaptic circuits in the brain are precisely organized, but the processes that govern this precision are poorly understood. Here we explored how distinct embryonic neural progenitor pools in the lateral ganglionic eminence (LGE) contribute to the synaptic circuit connectivity and neuronal diversity in the postnatal mouse striatum. In utero labeling of apical intermediate progenitors (aIP), as well as other progenitors (OP), revealed that both generate spiny projection neurons (SPNs), consisting of D1-expressing direct pathway (dSPNs) as well as D2-expressing indirect pathway (iSPNs) found intermingled in the medial aspects of striatum, with similar electrophysiological and anatomical properties. Subsequent optogenetic circuit-mapping of local synaptic connections between these SPNs showed that neurogenic stage rather than progenitor origin controls the strength of lateral GABAergic connections. However, embryonic progenitor origin conveyed strong biases in their long-range cortical inputs, in that aIP-derived SPNs were preferentially driven by inputs from the medial prefrontal cortex whereas OP-derived SPNs were strongly driven by inputs from the visual cortex. Combined, these results demonstrate critical roles for embryonic origin in shaping the inhibitory and excitatory synaptic circuits in the striatum.

Pathological synchronisation of beta frequency (12–35 Hz) oscillations between the subthalamic nucleus (STN) and cerebral cortex is thought to contribute to motor impairment in Parkinson's disease (PD). For this cortico-subthalamic oscillatory drive to be mechanistically important, it must influence the firing of STN neurons and, consequently, their downstream targets. Here, we examined the dynamics of synchronisation between STN LFPs and units with multiple cortical areas, measured using frontal ECoG, midline EEG and lateral EEG, during rest and movement. STN neurons lagged cortical signals recorded over midline (over premotor cortices) and frontal (over prefrontal cortices) with stable time delays, consistent with strong corticosubthalamic drive, and many neurons maintained these dynamics during movement. In contrast, most STN neurons desynchronised from lateral EEG signals (over primary motor cortices) during movement and those that did not had altered phase relations to the cortical signals. The strength of synchronisation between STN units and midline EEG in the high beta range (25–35 Hz) correlated positively with the severity of akinetic-rigid motor symptoms across patients. Together, these results suggest that sustained synchronisation of STN neurons to premotor-cortical beta oscillations play an important role in disrupting the normal coding of movement in PD., Highlights • Multi-channel EEG with coincident STN single unit and local field potential recordings • Variable time delays between beta oscillations in different cortical areas and STN neurons. • Frontal/premotor cortical areas have most stable oscillatory synchronisation with STN neurons. • Correlation between cortico-subthalamic beta-frequency synchronisation and clinical scores in PD.

Summary Synaptic circuits in the brain are precisely organized, but the processes that govern this precision are poorly understood. Here, we explore how distinct embryonic neural progenitor pools in the lateral ganglionic eminence contribute to neuronal diversity and synaptic circuit connectivity in the mouse striatum. In utero labeling of Tα1-expressing apical intermediate progenitors (aIP), as well as other progenitors (OP), reveals that both progenitors generate direct and indirect pathway spiny projection neurons (SPNs) with similar electrophysiological and anatomical properties and are intermingled in medial striatum. Subsequent optogenetic circuit-mapping experiments demonstrate that progenitor origin significantly impacts long-range excitatory input strength, with medial prefrontal cortex preferentially driving aIP-derived SPNs and visual cortex preferentially driving OP-derived SPNs. In contrast, the strength of local inhibitory inputs among SPNs is controlled by birthdate rather than progenitor origin. Combined, these results demonstrate distinct roles for embryonic progenitor origin in shaping neuronal and circuit properties of the postnatal striatum., Graphical abstract, Highlights • The Tα1 promoter distinguishes two embryonic progenitor pools in the LGE • Both pools generate intermixed spiny projection neurons in dorsomedial striatum • Excitatory cortical inputs are biased toward SPNs of different embryonic origin • Neurogenic stage rather impacts local inhibitory connections among SPNs, van Heusden et al. demonstrate significant roles for distinct embryonic progenitor pools in the formation of postnatal striatal synaptic circuits. Diverse progenitor pools generate striatal spiny projection neurons with similar intrinsic properties and convey biases in their excitatory cortical synaptic inputs, whereas birthdate affects strength of local inhibitory synaptic inputs.

Retrieving and acting upon memories of food-predicting environments are essential for survival. Pyramidal cells (PYRs) in dorsal CA1 hippocampus (dCA1) of the mammalian brain provide mnemonic representations of space. While dCA1 PYRs cannot directly access motor centers, the brain substrates by which these internal representations guide appetitive behavior are unknown. Here, we uncover a circuit motif embedded in the nucleus accumbens (NAc) that enables the behavioral readout of reward-place memories. By monitoring neuronal ensemble activity in mouse dCA1-NAc pathway, combined with cell-type-selective optogenetic manipulations of dCA1-input-defined postsynaptic neurons, we show that PYRs innervate and engage NAc parvalbumin-expressing fast-spiking interneurons (PV+ FSIs) to influence medium spiny neuron (MSN) firing and thus, NAc output. This motif is specialized for memory-guided appetitive behavior, being dispensable for spatial novelty detection and hedonic motivation. Our findings demonstrate that this PYR-PV+ FSI-MSN circuit motif instantiates a limbic-motor interface for hippocampal representations of space to promote behaviorally-effective appetitive memory.

The nucleus accumbens receives limbic inputs from a number of brain regions, including the ventral subiculum. In rats, activation of the ventral subiculum following microinjection of N-methyl-D-aspartate (NMDA) or carbachol increases locomotor activity, whilst ventral subiculum application of NMDA also increases dopamine efflux in the ipsilateral nucleus accumbens. Microdialysis experiments were therefore conducted to ascertain the consequences for dopamine release in the nucleus accumbens following ventral subiculum administration of carbachol, and to explore the acetylcholine receptor subtype(s) that might be involved. We report that, in anaesthetised rats, ventral subiculum administration of carbachol increased dopamine levels in the nucleus accumbens. The response was attenuated by co-administration with atropine, whilst administration of nicotine and the alpha-7 nicotinic acetylcholine receptor agonist AR-R17779 (spiro[1-azabicyclo[2,2,2]octane-3,5'-oxazolidine]-2'-one monohydrochloride) failed to evoke a response. Oxotremorine-M produced a dose-dependent increase in dopamine efflux confirming sensitivity to muscarinic receptor stimulation. However, the ventral subiculum was insensitive to xanomeline and pilocarpine, muscarinic M(1) receptor-preferring agonists, but sensitive to BuTAC ([5R-[exo]-6-[butylthio]-1,2,5-thiadiazol-3-yl]-1-azabicyclo[3.2.1])octane), a muscarinic M(2)/M(4) receptor agonist. The dopamine response to oxotremorine-M was significantly attenuated, although not abolished by co-administration with the M(2)/M(4) receptor antagonist methoctramine, and studies combining oxotremorine-M with (-)-bicuculline, indicated a dual action in the ventral subiculum that was dependent and independent of reduced GABA neurotransmission. The data presented indicates that activation of the ventral subiculum by carbachol increases dopamine efflux in the nucleus accumbens by stimulation of muscarinic receptors, and that the ventral subiculum-nucleus accumbens projection system is sensitive to muscarinic M(2)/M(4) receptor stimulation.

Hitherto, high-frequency local field potential oscillations in the upper gamma frequency band (40-80 Hz) have been recorded only from the region of subthalamic nucleus (STN) in parkinsonian patients treated with levodopa. Here we show that local field potentials recorded from the STN in the healthy alert rat also have a spectral peak in the upper gamma band (mean 53 Hz, range 46-70 Hz). The power of this high-frequency oscillatory activity was increased by 30 +/- 4% (+/-SEM) during motor activity compared to periods of alert immobility. It was also increased by 86 +/- 36% by systemic injection of the D2 dopamine receptor agonist quinpirole. The similarities between the high-frequency activities in the STN of the healthy rat and in the levodopa-treated parkinsonian human argue that this oscillatory activity may be physiological in nature and not a consequence of the parkinsonian state.