Neuroanatomy of autism: what is the role of the cerebellum?

Autism (or autism spectrum disorder) was initially defined as a psychiatric disorder, with the likely cause maternal behavior (the very destructive "refrigerator mother" theory). It took several decades for research into brain mechanisms to become established. Both neuropathological and imaging studies found differences in the cerebellum in autism spectrum disorder, the most widely documented being a decreased density of Purkinje cells in the cerebellar cortex.

Glycine is a transmitter in the human and chimpanzee cochlear nuclei.

Introduction: Auditory information is relayed from the cochlea via the eighth cranial nerve to the dorsal and ventral cochlear nuclei (DCN, VCN). The organization, neurochemistry and circuitry of the cochlear nuclei (CN) have been studied in many species. It is well-established that glycine is an inhibitory transmitter in the CN of rodents and cats, with glycinergic cells in the DCN and VCN.

Comparative analysis of four nuclei in the human brainstem: Individual differences, left-right asymmetry, species differences.

Introduction: It is commonly thought that while the organization of the cerebral cortex changes dramatically over evolution, the organization of the brainstem is conserved across species. It is further assumed that, as in other species, brainstem organization is similar from one human to the next. We will review our data on four human brainstem nuclei that suggest that both ideas may need modification.

Characterization of the superior olivary complex of chimpanzees (Pan troglodytes) in comparison to humans.

The superior olivary complex (SOC) is a collection of nuclei in the hindbrain of mammals with numerous roles in hearing, including localization of sound sources in the environment, encoding temporal and spectral elements of sound, and descending modulation of the cochlea. While there have been several investigations of the SOC in primates, there are discrepancies in the descriptions of nuclear borders and even the presence of certain cell groups among studies and species. Herein, we aimed to clarify some of these issues by characterizing the SOC from chimpanzees using Nissl staining, quantitative morphometry and immunohistochemistry.

Functional and Neuropathological Evidence for a Role of the Brainstem in Autism.

The brainstem includes many nuclei and fiber tracts that mediate a wide range of functions. Data from two parallel approaches to the study of autistic spectrum disorder (ASD) implicate many brainstem structures. The first approach is to identify the functions affected in ASD and then trace the neural systems mediating those functions.

Individual variability in the size and organization of the human arcuate nucleus of the medulla.

The arcuate nucleus (Arc) of the medulla is found in almost all human brains and in a small percentage of chimpanzee brains. It is absent in the brains of other mammalian species including mice, rats, cats, and macaque monkeys. The Arc is classically considered a precerebellar relay nucleus, receiving input from the cerebral cortex and projecting to the cerebellum via the inferior cerebellar peduncle.

The Claustrum in the Squirrel Monkey.

The claustrum (CLA) is a subcortical structure that is reciprocally and topographically connected with the cerebral cortex. The complexity of the cerebral cortex varies dramatically across mammals, raising the question of whether there might also be differences in CLA organization, circuitry, and function. Species variations in the shape of the CLA are well documented.

Species Differences in the Organization of the Ventral Cochlear Nucleus.

The mammalian cochlear nuclei (CN) consist of two major subdivisions, the dorsal (DCN) and ventral (VCN) nuclei. We previously reported differences in the structural and neurochemical organization of the human DCN from that in several other species. Here we extend this analysis to the VCN, considering both the organization of subdivisions and the types and distributions of neurons.

Individual variability in the structural properties of neurons in the human inferior olive.

The inferior olive (IO) is the sole source of the climbing fibers innervating the cerebellar cortex. We have previously shown both individual differences in the size and folding pattern of the principal nucleus (IOpr) in humans as well as in the expression of different proteins in IOpr neurons. This high degree of variability was not present in chimpanzee samples.

Laminar and neurochemical organization of the dorsal cochlear nucleus of the human, monkey, cat, and rodents.

The dorsal cochlear nucleus (DCN) is a brainstem structure that receives input from the auditory nerve. Many studies in a diversity of species have shown that the DCN has a laminar organization and identifiable neuron types with predictable synaptic relations to each other. In contrast, studies on the human DCN have found a less distinct laminar organization and fewer cell types, although there has been disagreement among studies in how to characterize laminar organization and which of the cell types identified in other animals are also present in humans.

Comparative organization of the claustrum: what does structure tell us about function?

The claustrum is a subcortical nucleus present in all placental mammals. Many anatomical studies have shown that its inputs are predominantly from the cerebral cortex and its outputs are back to the cortex. This connectivity thus suggests that the claustrum serves to amplify or facilitate information processing in the cerebral cortex.

Unique features of the human brainstem and cerebellum.

The cerebral cortex is greatly expanded in the human brain. There is a parallel expansion of the cerebellum, which is interconnected with the cerebral cortex. We have asked if there are accompanying changes in the organization of pre-cerebellar brainstem structures.

Tinnitus, unipolar brush cells, and cerebellar glutamatergic function in an animal model.

Unipolar brush cells (UBCs) are excitatory interneurons found in the dorsal cochlear nucleus (DCN) and the granule cell layer of cerebellar cortex, being particularly evident in the paraflocculus (PFL) and flocculus (FL). UBCs receive glutamatergic inputs and make glutamatergic synapses with granule cells and other UBCs. It has been hypothesized that UBCs comprise local networks of tunable feed-forward amplifiers.

Neurochemical organization of the vestibular brainstem in the common chimpanzee (Pan troglodytes).

Chimpanzees are one of the closest living relatives of humans. However, the cognitive and motor abilities of chimpanzees and humans are quite different. The fact that humans are habitually bipedal and chimpanzees are not implies different uses of vestibular information in the control of posture and balance.

A Mouse Model of Timothy Syndrome: a Complex Autistic Disorder Resulting from a Point Mutation in Cav1.2.

Timothy Syndrome (TS) arises from a point mutation in the human voltage-gated L-type Ca channel (Cav1.2). TS is associated with cardiac arrhythmias and sudden cardiac death, as well as congenital heart disease, impaired cognitive function, and autism spectrum disorders.

Understanding tinnitus: the dorsal cochlear nucleus, organization and plasticity.

Tinnitus, the perception of a phantom sound, is a common consequence of damage to the auditory periphery. A major goal of tinnitus research is to find the loci of the neural changes that underlie the disorder. Crucial to this endeavor has been the development of an animal behavioral model of tinnitus, so that neural changes can be correlated with behavioral evidence of tinnitus.

The nucleus pararaphales in the human, chimpanzee, and macaque monkey.

The human cerebral cortex and cerebellum are greatly expanded compared to those of other mammals, including the great apes. This expansion is reflected in differences in the size and organization of precerebellar brainstem structures, such as the inferior olive. In addition, there are cell groups unique to the human brainstem.

Neurochemical and structural organization of the principal nucleus of the inferior olive in the human.

The inferior olive (IO) is the sole source of the climbing fibers that innervate the Purkinje cells of the cerebellar cortex. The IO comprises several subdivisions, the dorsal accessory olive (DAO), medial accessory olive (MAO), and principal nuclei of the IO (IOpr); the relative sizes of these subnuclei vary among species. In human, there is an expansion of the cerebellar hemispheres and a corresponding expansion of the IOpr.

Nonphosphorylated neurofilament protein is expressed by scattered neurons in the human vestibular brainstem.

Vestibular information is critical for the maintenance of balance and posture and for the control of eye movements. The eighth nerve carries vestibular information to four brainstem nuclei called the vestibular nuclear complex (VNC); these nuclei relay vestibular signals to several additional brainstem nuclei. The structure, connections, effects of lesions and neuronal response properties of the vestibular brainstem have been studied in many nonhuman species.

Otolith stimulation induces c-Fos expression in vestibular and precerebellar nuclei in cats and squirrel monkeys.

Vestibular information is critical for the control of balance, posture, and eye movements. Signals from the receptors, the semicircular canals and otoliths, are carried by the eighth nerve and distributed to the four nuclei of the vestibular nuclear complex, the VNC. However, anatomical and physiological data suggest that many additional brainstem nuclei are engaged in the processing of vestibular signals and generation of motor responses.

Expression of calcium-binding proteins and nNOS in the human vestibular and precerebellar brainstem.

Information about the position and movement of the head in space is coded by vestibular receptors and relayed to four nuclei that comprise the vestibular nuclear complex (VNC). Many additional brainstem nuclei are involved in the processing of vestibular information, receiving signals either directly from the eighth nerve or indirectly via projections from the VNC. In cats, squirrel monkeys, and macaque monkeys, we found neurochemically defined subdivisions within the medial vestibular nucleus (MVe) and within the functionally related nucleus prepositus hypoglossi (PrH).

L-Serine-O-phosphate in the central nervous system.

L-serine-O-phosphate (L-SOP) is the immediate precursor to L-serine in the serine synthesis pathway and is also an agonist at the Group III metabotropic glutamate receptors (mGluRs). L-SOP is produced by the enzyme phosphoserine aminotransferase (PSAT) and metabolized to L-serine by phosphoserine phosphatase (PSP). Using a novel analytical procedure, we show that L-SOP is present in rat whole brain, and that in transfected cells, it is substantially more potent than L-glutamate at the mGluR4 receptor subtype.