Hypothalamic innervation of the claustrum: Implications for memory, spatial navigation, and sleep-wake regulation

The posterior hypothalamus comprises several structures involved in memory formation. Among these, neuronal populations of the lateral hypothalamus, such as melanin-concentrating hormone (MCH) neurons, and the mammillary nuclei have been extensively studied. Several of these structures or populations project to the claustrum, a small subcortical region with extensive cortical connections. It has been hypothesized that the claustrum plays a pivotal role in consciousness and cognitive integration, suggesting an indirect or complementary role in mnemonic processes. However, the role of hypothalamic-claustral connections has been largely neglected. Therefore, the objective of this review is to analyze the projection patterns from specific hypothalamic tuberal neuron populations (MCH, orexin, histamine) and the supramammillary nucleus (SUM) to the claustrum, to determine whether these anatomical features can provide insights into their potential functions and stimulate further research in this domain. The SUM provides robust, specific projections to the claustrum, suggesting that these projections are part of a specialized network. Given that both the claustrum and SUM connect to the hippocampus and prefrontal cortex, it is plausible that the SUM-claustrum pathway plays a role in spatial memory encoding and representation. In contrast, the tuberal lateral hypothalamus exhibits a different projection pattern to the claustrum. MCH neurons provide significant diffuse innervation to this nucleus and surrounding cortex, while histaminergic and orexinergic projections are more scattered, targeting mostly adjacent tissues. The distribution of various receptors for these neuropeptides and neurotransmitters within the claustrum suggests functional relevance in regulating non-specific modulation of neuronal activity. These projections may be more closely related to sleep-wake regulation and, consequently, to the consolidation of episodic memory. This review highlights that hypothalamic projections to the claustrum illustrate the dual role of this small structure at the intersection of cognitive and physiological processes. The claustrum, involved in arousal and episodic memory on one hand, and spatial navigation associated with specific behavioral expression on the other, could be conceptualized as an integrative hub that coordinates cortical activity according to behavioral state (sleep/wake) through convergent cortical and subcortical inputs.