Kenichiro Negishi

The claustrum is among the most highly interconnected structures in the mammalian brain, with reciprocal projections spanning the cortical mantle and a growing roster of functions that range from sleep regulation to attentional control. Here we review current understanding of claustral circuit organization and function, synthesizing findings from anatomical, physiological, computational, and behavioral studies. We argue that a unifying logic underlies the apparent diversity of claustral functions: the claustrum operates through projection-defined subnetworks whose input selectivity, output targets, and local circuit interactions collectively determine their functional contribution and whose impact on cortical targets varies with arousal and ongoing brain state. Corticoclaustral connectivity is organized into matched inputoutput modules, local inhibitory circuits confer spatial filtering properties that amplify strong cortical signals while suppressing weaker ones and claustral output populations differ in their laminar targets, postsynaptic cell-type preferences, and molecular properties, producing diverse and context-dependent effects on cortical dynamics. These circuit properties translate into claustral regulation of cortical population dynamics across multiple timescales, from the moment-to-moment coordination of brain states to the consolidation of frontal control strategies. In pain and addiction, specific claustral projection populations are selectively dysregulated, and distinct subnetworks exert opposing influences on nociceptive sensitivity and drug-related behavior according to their cortical targets. Together, these findings position the claustrum as a modular subcortical hub for the selective regulation of distributed cortical networks and identify it as a candidate therapeutic target for disorders characterized by dysregulated cortical network activity, including chronic pain, addiction, and impulsivity.

Anatomical studies suggest that a dorsomedial region of the nucleus accumbens (dmACB) forms a basal ganglia‐like closed‐loop circuit with medial ventral pallidum (mVP), lateral hypothalamic area (LHA), and paraventricular thalamic nucleus (PVT). The circuit's topographic organization is unknown. We first used anterograde ( Phaseolus vulgaris leucoagglutinin, PHAL) and retrograde (cholera toxin B, CTB) tracers to map this organization. We then used immunoreactivity for Fos phosphorylated at serine 32 (pSer32‐Fos‐ir; hereafter “Fos”) as a proxy for the activation marker Fos to determine whether the time‐dependent increase (incubation) of oxycodone seeking after electric barrier‐induced abstinence is associated with dmACB activation. In Experiment 1, we injected rats with PHAL into the anterior PVT (aPVT) and CTB into either the mVP or the anterior LHA (LHAa) to determine the distribution of their connections within the dmACB. We also injected CTB into the anterior and posterior dmACB to identify afferent inputs. In Experiment 2, we trained rats to self‐administer oxycodone for 2 weeks and counted Fos‐labeled cells in anterior and posterior dmACB, the surrounding ACB, and dorsal striatum regions after drug‐seeking tests on either abstinence Day 1 or Day 15 following electric barrier‐induced abstinence. PHAL‐labeled aPVT axons and CTB‐labeled mVP and LHA neurons were confined to dmACB, forming a longitudinal column along the anterior–posterior axis of ACB. Inputs to anterior and posterior dmACB came from different cortical and subcortical regions. dmACB Fos+ cell counts were higher after oxycodone‐seeking tests on Day 1 than on Day 15 and were negatively correlated with oxycodone seeking. These results characterize a connection‐defined dmACB circuit and show that incubation of opioid‐seeking is unexpectedly associated with reduced dmACB activation.

The claustrum is among the most highly interconnected structures in the mammalian brain, with reciprocal projections spanning the cortical mantle and a growing roster of functions that range from sleep regulation to attentional control. Here we review current understanding of claustral circuit organization and function, synthesizing findings from anatomical, physiological, computational, and behavioral studies. We argue that a unifying logic underlies the apparent diversity of claustral functions: the claustrum operates through projection-defined subnetworks whose input selectivity, output targets, and local circuit interactions collectively determine their functional contribution, and whose impact on cortical targets varies with arousal and ongoing brain state. Corticoclaustral connectivity is organized into matched input-output modules, local inhibitory circuits confer spatial filtering properties that amplify strong cortical signals while suppressing weaker ones, and claustral output populations differ in their laminar targets, postsynaptic cell-type preferences, and molecular properties, producing diverse and context-dependent effects on cortical dynamics. These circuit properties translate into claustral regulation of cortical population dynamics across multiple timescales, from the moment-to-moment coordination of brain states to the consolidation of frontal control strategies. In pain and addiction, specific claustral projection populations are selectively dysregulated, and distinct subnetworks exert opposing influences on nociceptive sensitivity and drug-related behavior according to their cortical targets. Together, these findings position the claustrum as a modular subcortical hub for the selective regulation of distributed cortical networks and identify it as a candidate therapeutic target for disorders characterized by dysregulated cortical network activity, including chronic pain, addiction, and impulsivity.

Growth hormone secretagogue receptors (GHSRs) modulate reward and cost processing separately, but their role in conflict-based decision-making is unclear. We observed dose-dependent effects of the GHSR agonist ibutamoren (IBU) on rat decision-making performance. Moderate, but not low or high doses, increased cost sensitivity selectively in conflict paradigms. We observed dense GHSR expression in dorsomedial striosomes, a region critical for conflict decision-making. Moderate GHSR activation increased neuronal activity in dorsomedial striosomes that project to lateral habenula (LHb) and enhanced inactivation of dopaminergic neurons in the substantia nigra pars compacta (daSNc). Chemogenetic manipulation of dorsomedial striosomes activity confirmed their causal influence on both GHSR-mediated increases in cost-sensitivity and circuit activity in LHb and daSNc. Our results identify a novel circuit mechanism linking endocrine activity with conflict decision-making.

Optimal decision-making requires consideration of internal and external contexts. Biased decision-making is a transdiagnostic symptom of neuropsychiatric disorders. We created a computational model demonstrating how the striosome compartment of the striatum constructs a context-dependent mathematical space for decision-making computations, and how the matrix compartment uses this space to define action value. The model explains multiple experimental results and unifies other theories like reward prediction error, roles of the direct versus indirect pathways, and roles of the striosome versus matrix, under one framework. We also found, through new analyses, that striosome and matrix neurons increase their synchrony during difficult tasks, caused by a necessary increase in dimensionality of the space. The model makes testable predictions about individual differences in disorder susceptibility, decision-making symptoms shared among neuropsychiatric disorders, and differences in neuropsychiatric disorder symptom presentation. The model provides evidence for the central role that striosomes play in neuroeconomic and disorder-affected decision-making.

The zona incerta (ZI) supports diverse behaviors including binge feeding, sleep–wake cycles, nociception, and hunting. Diverse ZI functions can be attributed to its heterogeneous neurochemical characterization, cytoarchitecture, and efferent connections. The ZI is predominantly GABAergic, but we recently identified a subset of medial ZI GABA cells that are marked by the enzyme tyrosine hydroxylase (TH) and produce dopamine (DA). While the role of GABA within the ZI is well studied, less is known about the functions of ZI DA cells. To identify potential roles of ZI DA cells, we further phenotyped them and mapped their efferent fiber projections. We showed that wild‐type TH‐immunoreactive (‐ir) ZI cells did not express somatostatin or calretinin immunoreactivity. We next validated a Th‐cre;L10‐Egfp mouse line and found that medial Egfp ZI cells were more likely to be TH‐ir. We therefore delivered a Cre‐dependent virus into the medial ZI of Th‐cre or Th‐cre;L10‐Egfp mice and selected two injection cases for full brain mapping, namely, cases with the lowest and highest colocalization between TH‐ir and virally transduced, DsRed‐labeled cells, to identify common target sites. Overall, DsRed‐labeled fibers were distributed brainwide and were most prominent within the motor‐related midbrain (MBmot), notably the periaqueductal gray area and superior colliculus. We also observed numerous DsRed‐labeled fibers within the polymodal association cortex‐related thalamus (DORpm), like paraventricular thalamic nucleus and nucleus of reunions, that processes external and internal sensory input. Overall, ZI DA cells displayed a similar fiber profile to ZI GABA cells and may integrate sensory input to coordinate motor output at their target sites.

We previously reported that ventral subiculum (vSub) activity is critical to incubation of oxycodone seeking after abstinence induced by adverse consequences of drug seeking. Here, we studied the role of claustrum, a key vSub input, in this incubation. We trained male and female rats to self-administer oxycodone for 2 weeks and then induced abstinence by exposing them to an electric barrier for 2 weeks. We used retrograde tracing (cholera toxin B subunit) plus the activity marker Fos to identify projections to vSub cactivated during “incubated” relapse (Abstinence Day 15). We then used pharmacological reversible inactivation to determine the causal role of claustrum in incubation and the behavioral and anatomical specificity of this role. We also used an anatomical disconnection procedure to determine the causal role of claustrum–vSub connections in incubation. Finally, we analyzed an existing functional MRI dataset to determine if functional connectivity changes in claustrum-related circuits predict incubation of oxycodone seeking. Claustrum neurons projecting to vSub were activated during relapse tests after electric barrier-induced abstinence. Inactivation of claustrum but not areas dorsolateral to claustrum decreased incubation of oxycodone seeking after electric barrier-induced abstinence; claustrum inactivation had no effect on incubation after food choice-induced abstinence. Both ipsilateral and contralateral inactivation of claustrum–vSub projections decreased incubation after electric barrier-induced abstinence. Functional connectivity changes in claustrum–cortical circuits during electric barrier-induced abstinence predicted incubated oxycodone relapse. Our study identified a novel role of claustrum in relapse to opioid drugs after abstinence induced by adverse consequences of drug seeking.

The medial prefrontal cortex [ cingulate region (Brodmann, 1909) (CNG)] in the rat is a connectionally and functionally diverse structure. It harbors cerebral nuclei that use long-range connections to promote adaptive changes to ongoing behaviors. The CNG is often described across functional and anatomical gradients, a dorsal-ventral gradient being the most prominent. Topographic organization is a general feature of the nervous system, and it is becoming clear that such spatial arrangements can reflect connectional, functional, and cellular differences. Portions of the CNG are known to form reciprocal connections with cortical areas and thalamus; however, these connectional features have not been described in detail or mapped to standardized rat brain atlases. Here, we used co-injected anterograde ( Phaseolus vulgaris leucoagglutinin) and retrograde (cholera toxin B subunit) tracers throughout the CNG to identify zones of reciprocal connectivity in the diencephalon [or interbrain (Baer, 1837) (IB)]. Tracer distributions were observed using a Nissl-based atlas-mapping approach that facilitates description of topographic organization. This draft report describes CNG connections of the infralimbic area (Rose & Woolsey, 1948) (ILA) and the anterior cingulate area, dorsal part (Krettek & Price, 1977) (ACAd) throughout the IB. We found that corticothalamic connections are predominantly reciprocal, and that ILA and ACAd connections tended to be spatially segregated with minimal overlap. In the hypothalamus (Kuhlenbeck, 1927) , we found dense and specific ILA-originating terminals in the following Brain Maps 4.0 at las territories: dorsal region (Swanson, 2004) (LHAd) and suprafornical region (Swanson, 2004) (LHAs) of the lateral hypothalamic area (Nissl, 1913) , parasubthalamic nucleus (Wang & Zhang, 1995) (PSTN), tuberal nucleus, terete part (Petrovich et al., 2001) (TUte), and an ill-defined dorsal cap of the medial mammillary nucleus (Gudden, 1881) (MM). We discuss these findings in the context of feeding behaviors.