The Red Nucleus (RN) is a primitive brainstem structure located in the ventral midbrain. Histologically, the RN consists of two distinct structures: a caudal parvocellular red nucleus (RNp) and a rostral magnocellular red nucleus (RNm).[1][2] Although the origin of the RN is not completely understood, studies suggest it can be attributed to the evolutionary development of limbs and locomotion among vertebrates.[3] Specifically, when comparing different species, there is wide variability in both the structure and function of the RN. Generally speaking, the RNm predominates in lower vertebrates, while the RNp is more prominent in higher species.[2] With regards to quadrupedal mammals (i.e., cats and rats), the RNm is highly developed. However, when progressing upward the evolutionary pyramid, the RNm decreases in size and ultimately bares minimal significant volume or neurological function within the human brain (conversely, the RNp occupies most of the RN total volume in humans).[1][4][5][6] Furthermore, although the two subsections of the RN are virtually undifferentiated in lower mammals, the human RNm and RNp are so distinct that they are more so considered two completely independent structures altogether.[2]

As mentioned previously, the RN is subdivided into the RNp and the RNm. Both of these neurons are arranged in a somatotopic distribution, with the upper limb corresponding with the dorsomedial region, and the lower limb correlating with the ventrolateral portion.[7][1] With regards to the RNm, the contralateral interposed nuclei of the deep cerebellum projects neurons that travel directly to the RNm, which thereby gives rise to the rubrospinal tract and subsequently relays into the spinal cord.[1] Conversely, the RNp receives input from the dentate nucleus within the cerebral cortex as well as the deep white matter of the cerebellum and redirects input into the ipsilateral inferior olivary nucleus (commonly referred to as the myoclonic triangle, the Triangle of Guillain-Mollaret, or the dentato-rubro-olivary pathway).[1]

It is important to distinguish the subsections of the red nuclei because each possesses a unique neuronal pathway, and therefore dictates a separate neurologic function. For example, among quadrupedal animals, the RNm closely mirrors the pyramidal tract when animals navigate through obstacles and perform various coordinated extremity movements.[8] In upper mammals (such as primates) rubrospinal activity (and therefore RNm activity) influences more primitive motor activity such as grasping, most prominently among infants.[9] As mentioned previously, the RNm is largely rudimentary in adult humans (and therefore bears a lesser neurologic role), most likely due to the development (and functional redundancy) of the corticospinal tract as well as the pyramidal system.[9][10] One interesting correlation to note is that among fetuses and newborns, who possess a particularly notable magnocellular red neurons, also demonstrate particularly prominent limb flexor tone.[9] Additionally, anencephalic infants deprived of the cerebral cortex (but still have intact midbrain and therefore, an RN) can exhibit synergistic stepping patters, therefore reinforcing the notion that the rubrospinal tract bears functional responsibility in primitive movements.[11]

In contrast, the RNp provides an important connection between the motor and premotor cortices as well as the cerebellum, and inputs directly into the inferior olivary nucleus.[9] Therefore, this subsection of the RN represents an important link in the motor circuit. Although the exact role of the RNp remains unknown, it is suggested to potentially play a role in complex cognitive-motor functions by regulating the olivocerebellar tract system.[12][13]

In summary, the parvocellular division of the RN is particularly prominent in the adult human brain and may play a role in cognitive-motor function, while the magnocellular RN only demonstrates functional relevance in early development through primitive movements, and becomes less functionally significant with aging.[9]

To date, there are very few studies exploring the embryonic development of the red neuron.[6][2] However, studies that have examined such development noted several consistent findings. First, initial development commences with cell migration concurrently with the mid-brain from the cerebellum at around week 7. Around week 8, cells accumulate along the cerebellar outgrowth, which eventually develops into the dentate nucleus in series with the RN. After that, RN differentiation commences with RNm formation beginning around 12 weeks.[2] By week 14, large and small neurons are recognizable within the RN and continue to develop into the RNm and the RNp. Between weeks 18-23, the oculomotor nerve localizes and clusters around the RN[2] and eventually distributes along the ventrolateral superior cerebellar peduncle from 28 weeks onward. Finally, from weeks 28 to 33, there is a near-linear increase in neuronal size with regards to gestational age, leading to ultimately a consistent detection of neuro-histology by 33 weeks.[2]

 The RN receives blood supply from the Posterior Cerebral Artery (PCA).[14][15][14]

There is an increasing number of studies exploring the relationship between the magnocellular RN and pain modulation and allodynia,[16][17] most likely via inflammatory cytokine expression through the JAK/STAT, JNK, ERK signaling cascade.[18][19] As such, previous studies have demonstrated that spared nerve injury in animal models up-regulate pro-inflammatory cytokines (such as interleukin-6 and tumor necrosis factor-alpha) within the red nucleus. Furthermore, the administration of recombinant pro-inflammatory cytokines directly within the RN can evoke tactile allodynia.[19][20] Conversely, inhibition of such cytokines can mitigate neuropathic pain[21][22] and relieve subsequent spared nerve injury tactile allodynia.[23][24][25] The combination of these findings suggests a causal relationship between the red nucleus and pain modulation.