The Claustrum-Prefrontal Cortex Pathway Regulates Impulsive-Like Behavior.

The claustrum connects with a broad range of cortical areas including the prefrontal cortex (PFC). However, the function of the claustrum (CLA) and its neural projections remains largely unknown. Here, we elucidated the role of the neural projections from the CLA to the PFC in regulating impulsivity in male rats. We first identified the CLA-PFC pathway by retrograde tracer and virus expression. By using immunofluorescent staining of the c-Fos-positive neurons, we showed that chemogenetic activation and inhibition of the CLA-PFC pathway reduced and increased overall activity of the PFC, respectively. In the 5-choice serial reaction time task (5-CSRTT), we found that chemogenetic activation and inhibition of the CLA-PFC pathway increased and reduced the impulsive-like behavior (i.e., premature responses), respectively. Furthermore, chemogenetic inhibition of the CLA-PFC pathway prevented methamphetamine-induced impulsivity, without affecting methamphetamine-induced hyperactivity. In contrast to the role of CLA-PFC pathway in selectively regulating impulsivity, activation of the claustrum disrupted attention in the 5-CSRTT. These results indicate that the CLA-PFC pathway is essential for impulsivity. This study may shed light on the understanding of impulsivity-related disorders such as drug addiction.SIGNIFICANCE STATEMENT The claustrum is one of the most mysterious brain regions. Although extensive anatomical studies demonstrated that the claustrum connects with many cortical areas, the function of the neural projections between the claustrum and cortical areas remain largely unknown. Here, we showed that the neural projections from the claustrum to the prefrontal cortex regulates impulsivity by using the designer drugs (DREADDs)-based chemogenetic tools. Interestingly, the claustrum-prefrontal cortex pathway also regulates methamphetamine-induced impulsivity, suggesting a critical role of this neural pathway in regulating impulsivity-related disorders such as drug addiction. Our results provided preclinical evidence that the claustrum-prefrontal cortex regulates impulsivity. The claustrum-prefrontal cortex pathway may be a novel target for the treatment of impulsivity-related brain disorders.

Psilocybin acutely alters the functional connectivity of the claustrum with brain networks that support perception, memory, and attention.

Psychedelic drugs, including the serotonin 2a (5-HT2A) receptor partial agonist psilocybin, are receiving renewed attention for their possible efficacy in treating a variety of neuropsychiatric disorders. Psilocybin induces widespread dysregulation of cortical activity, but circuit-level mechanisms underlying this effect are unclear. The claustrum is a subcortical nucleus that highly expresses 5-HT2A receptors and provides glutamatergic inputs to arguably all areas of the cerebral cortex. We therefore tested the hypothesis that psilocybin modulates claustrum function in humans. Fifteen healthy participants (10M, 5F) completed this within-subjects study in which whole-brain resting-state blood-oxygenation level-dependent (BOLD) signal was measured 100 â€‹min after blinded oral administration of placebo and 10 mg/70 â€‹kg psilocybin. Left and right claustrum signal was isolated using small region confound correction. Psilocybin significantly decreased both the amplitude of low frequency fluctuations as well as the variance of BOLD signal in the left and right claustrum. Psilocybin also significantly decreased functional connectivity of the right claustrum with auditory and default mode networks (DMN), increased right claustrum connectivity with the fronto-parietal task control network (FPTC), and decreased left claustrum connectivity with the FPTC. DMN integrity was associated with right-claustrum connectivity with the DMN, while FPTC integrity and modularity were associated with right claustrum and left claustrum connectivity with the FPTC, respectively. Subjective effects of psilocybin predicted changes in the amplitude of low frequency fluctuations and the variance of BOLD signal in the left and right claustrum. Observed effects were specific to claustrum, compared to flanking regions of interest (the left and right insula and putamen). This study used a pharmacological intervention to provide the first empirical evidence in any species for a significant role of 5-HT2A receptor signaling in claustrum functioning, and supports a possible role of the claustrum in the subjective and therapeutic effects of psilocybin.

Mice Lacking Connective Tissue Growth Factor in the Forebrain Exhibit Delayed Seizure Response, Reduced C-Fos Expression and Different Microglial Phenotype Following Acute PTZ Injection.

Connective tissue growth factor (CTGF) plays important roles in the development and regeneration of the connective tissue, yet its function in the nervous system is still not clear. CTGF is expressed in some distinct regions of the brain, including the dorsal endopiriform nucleus (DEPN) which has been recognized as an epileptogenic zone. We generated a forebrain-specific Ctgf knockout (FbCtgf KO) mouse line in which the expression of Ctgf in the DEPN is eliminated. In this study, we adopted a pentylenetetrazole (PTZ)-induced seizure model and found similar severity and latencies to death between FbCtgf KO and WT mice. Interestingly, there was a delay in the seizure reactions in the mutant mice. We further observed reduced c-fos expression subsequent to PTZ treatment in the KO mice, especially in the hippocampus. While the densities of astrocytes and microglia in the hippocampus were kept constant after acute PTZ treatment, microglial morphology was different between genotypes. Our present study demonstrated that in the FbCtgf KO mice, PTZ failed to increase neuronal activity and microglial response in the hippocampus. Our results suggested that inhibition of Ctgf function may have a therapeutic potential in preventing the pathophysiology of epilepsy.

Claustral Neurons Projecting to Frontal Cortex Mediate Contextual Association of Reward.

The claustrum is a small nucleus, exhibiting vast reciprocal connectivity with cortical, subcortical, and midbrain regions. Recent studies, including ours, implicate the claustrum in salience detection and attention. In the current study, we develop an iterative functional investigation of the claustrum, guided by quantitative spatial transcriptional analysis. Using this approach, we identify a circuit involving dopamine-receptor expressing claustral neurons projecting to frontal cortex necessary for context association of reward. We describe the recruitment of claustral neurons by cocaine and their role in drug sensitization. In order to characterize the circuit within which these neurons are embedded, we apply chemo- and opto-genetic manipulation of increasingly specified claustral subpopulations. This strategy resolves the role of a defined network of claustrum neurons expressing dopamine D1 receptors and projecting to frontal cortex in the acquisition of cocaine conditioned-place preference and real-time optogenetic conditioned-place preference. In sum, our results suggest a role for a claustrum-to-frontal cortex circuit in the attribution of incentive salience, allocating attention to reward-related contextual cues.

The claustrum is a target for projections from the supramammillary nucleus in the rat.

Injection of the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHAL) into the rat rostral and caudal supramammillary nucleus (SUM) provided expected patterns of projections into the hippocampus and the septal region. In addition, unexpectedly intense projections were observed into the claustrum defined by parvalbumin expression. Injections of the retrograde tracer fluorogold (FG) into the hippocampus and the region of the claustrum showed that the cells of origin of these projections distributed similarly within the borders of the SUM. The SUM is usually involved in control of hippocampal theta activity, but the observation of intense projections into the claustrum indicates that it may also influence isocortical processes. Therefore, the SUM may coordinate sensory processing in the isocortex with memory formation in the hippocampus.