SUMMARY A striking neurochemical form of compartmentalization has been found in the striatum of humans and other species, dividing it into striosomes and matrix. The function of this organization has been unclear, but the anatomical connections of striosomes indicate their relation to emotion-related brain regions including the medial prefrontal cortex. We capitalized on this fact by combining pathway-specific optogenetics and electrophysiology in behaving rats to search for selective functions of striosomes. We demonstrate that a medial prefronto-striosomal circuit is selectively active in and causally necessary for cost-benefit decision-making under approach-avoidance conflict conditions known to evoke anxiety in humans. We show that this circuit has unique dynamic properties likely reflecting striatal interneuron function. These findings demonstrate that cognitive and emotion-related functions are, like sensory-motor processing, subject to encoding within compartmentally organized representations in the forebrain, and suggest that striosome-targeting corticostriatal circuits can underlie neural processing of decisions fundamental for survival.

SUMMARY Effective evaluation of costs and benefits is a core survival capacity that in humans is considered as optimal, ’rational’ decision-making. This capacity is vulnerable in neuropsychiatric disorders and in the aftermath of chronic stress, in which aberrant choices and high-risk behaviors occur. We report that chronic stress exposure in rodents produces abnormal evaluation of costs and benefits resembling non-optimal decision-making in which choices of high-cost/high-reward options are sharply increased. Concomitantly, alterations in the task-related spike activity of medial prefrontal neurons correspond to increased activity of their striosome-predominant striatal projection neuron targets and to decreased and delayed striatal fast-firing interneuron activity. These effects of chronic stress on prefronto-striatal circuit dynamics could be blocked, or be mimicked, by selective optogenetic manipulation of these circuits. We suggest that altered excitation-inhibition dynamics of striosome-based circuit function could be an underlying mechanism by which chronic stress contributes to disorders characterized by aberrant decision-making under conflict.

The circuitry of the striatum is characterized by two organizational plans: the division into striosome and matrix compartments, thought to mediate evaluation and action, and the direct and indirect pathways, thought to promote or suppress behavior. The developmental origins of these organizations and their developmental relationships are unknown, leaving a conceptual gap in understanding the cortico-basal ganglia system. Through genetic fate mapping, we demonstrate that striosome-matrix compartmentalization arises from a lineage program embedded in lateral ganglionic eminence radial glial progenitors mediating neurogenesis through two distinct types of intermediate progenitors (IPs). The early phase of this program produces striosomal spiny projection neurons (SPNs) through fate-restricted apical IPs (aIPs) with limited capacity; the late phase produces matrix SPNs through fate-restricted basal IPs (bIPs) with expanded capacity. Notably, direct and indirect pathway SPNs arise within both aIP and bIP pools, suggesting that striosome-matrix architecture is the fundamental organizational plan of basal ganglia circuitry.

We propose here that the modular organization of the striatum reflects a context-sensitive modular learning architecture in which clustered striosome–matrisome domains participate in modular reinforcement learning (RL). Based on anatomical and physiological evidence, it has been suggested that the modular organization of the striatum could represent a learning architecture. There is not, however, a coherent view of how such a learning architecture could relate to the organization of striatal outputs into the direct and indirect pathways of the basal ganglia, nor a clear formulation of how such a modular architecture relates to the RL functions attributed to the striatum. Here, we hypothesize that striosome–matrisome modules not only learn to bias behavior toward specific actions, as in standard RL, but also learn to assess their own relevance to the environmental context and modulate their own learning and activity on this basis. We further hypothesize that the contextual relevance or “responsibility” of modules is determined by errors in predictions of environmental features and that such responsibility is assigned by striosomes and conveyed to matrisomes via local circuit interneurons. To examine these hypotheses and to identify the general requirements for realizing this architecture in the nervous system, we developed a simple modular RL model. We then constructed a network model of basal ganglia circuitry that includes these modules and the direct and indirect pathways. Based on simple assumptions, this model suggests that while the direct pathway may promote actions based on striatal action values, the indirect pathway may act as a gating network that facilitates or suppresses behavioral modules on the basis of striatal responsibility signals. Our modeling functionally unites the modular compartmental organization of the striatum with the direct–indirect pathway divisions of the basal ganglia, a step that we suggest will have important clinical implications.

We discuss a biophysical model of synaptic plasticity that provides a unified view of the outcomes of synaptic modification protocols, including: (1) prescribed time courses of postsynaptic intracellular Ca(2+) release, (2) postsynaptic voltage clamping with presentation of presynaptic spike trains at various frequencies, (3) direct postsynaptic response to presynaptic spike trains at various frequencies, and (4) LTP/LTD as a response to precisely timed presynaptic and postsynaptic spikes.

The telencephalic premotor nucleus HVC is situated at a critical point in the pattern-generating premotor circuitry of oscine songbirds. A striking feature of HVC's premotor activity is that its projection neurons burst extremely sparsely. Here we present a computational model of HVC embodying several central hypotheses: 1) sparse bursting is generated in bistable groups of recurrently connected robust nucleus of the arcopallium (RA)-projecting (HVCRA) neurons; 2) inhibitory interneurons terminate bursts in the HVCRA groups; and 3) sparse sequences of bursts are generated by the propagation of waves of bursting activity along networks of HVCRA neurons. Our model of sparse bursting places HVC in the context of central pattern generators and cortical networks using inhibition, recurrent excitation, and bistability. Importantly, the unintuitive result that inhibitory interneurons can precisely terminate the bursts of HVCRA groups while showing relatively sustained activity throughout the song is made possible by a specific constraint on their connectivity. We use the model to make novel predictions that can be tested experimentally.

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Uncovering the roles of neural feedback in the brain is an active area of experimental research. In songbirds, the telencephalic premotor nucleus HVC receives neural feedback from both forebrain and brain stem areas. Here we present a computational model of birdsong sequencing that incorporates HVC and associated nuclei and builds on the model of sparse bursting presented in our preceding companion paper. Our model embodies the hypotheses that 1) different networks in HVC control different syllables or notes of birdsong, 2) interneurons in HVC not only participate in sparse bursting but also provide mutual inhibition between networks controlling syllables or notes, and 3) these syllable networks are sequentially excited by neural feedback via the brain stem and the afferent thalamic nucleus Uva, or a similar feedback pathway. We discuss the model's ability to unify physiological, behavioral, and lesion results and we use it to make novel predictions that can be tested experimentally. The model suggests a neural basis for sequence variations, shows that stimulation in the feedback pathway may have different effects depending on the balance of excitation and inhibition at the input to HVC from Uva, and predicts deviations from uniform expansion of syllables and gaps during HVC cooling.