Anatomical and physiological properties of the superior paraolivary nucleus in the rat

The superior paraolivary nucleus (SPON) is a group of neurons located within the superior olivary complex, a constellation of brainstem nuclei involved in auditory processing. The major inputs to the SPON arise from the contralateral ear and SPON axons target primarily the ipsilateral inferior colliculus. However, little is known regarding the neurochemical phenotypes present in the SPON and how these neurons respond to auditory stimuli. Understanding the neurochemical and physiological properties of the constituent neurons will provide insight into the functional role of the SPON and will contribute to our understanding of the neural circuitry involved in hearing. Immunocytochemical, stereological, physiological and pharmacological techniques were used to characterize SPON neurons in the rat. The presence of inhibitory neurotransmitters was investigated with immunocytochemistry and provides evidence that the SPON contains a morphologically homogeneous population of GABAergic neurons and further that these neurons receive a robust inhibitory innervation in the form of glycinergic and GABAergic inputs. Stereological estimates of total neuron number in eighteen subcortical auditory nuclei provide evidence that the SPON is a prominent brainstem cell group and a major source of ascending inhibition to the inferior colliculus. Extracellular in vivo recordings provide evidence that nearly all SPON neurons respond to sound played in the contralateral ear with spike activity timed to the stimulus offset and phase lock to amplitude modulations in complex sounds. Pharmacologically blocking glycinergic input abolished the offset response (indicating that offset activity is a rebound from glycinergic inhibition); blockade of glycinergic and GABAergic input simultaneously, resulted in broader receptive fields and reduced phase locking capabilities. Taken together, these data indicate the rat SPON is a prominent auditory cell group that provides GABAergic inhibition to the ipsilateral inferior colliculus indicating the sound offset. GABAergic inhibition has been implicated in numerous aspects of auditory physiology, including sound localization and sensitivity to stimulus duration. Therefore, the SPON plays an important role in auditory processing and offset inhibition may be involved in processing complex sounds and in creating sensitivity to stimulus duration, both important features of animal and human communication

Distribution of Glutamatergic and Glycinergic Inputs onto Human Auditory Coincidence Detector Neurons.

Localization of sound sources in the environment requires neurons that extract interaural timing differences (ITD) in low-frequency hearing animals from fast and precisely timed converging inputs from both ears. In mammals, this is accomplished by neurons in the medial superior olive (MSO). MSO neurons receive converging excitatory input from both the ipsilateral and contralateral cochlear nuclei and glycinergic, inhibitory input by way of interneurons in the medial and lateral nuclei of the trapezoid body (MNTB and LNTB, respectively). Key features of the ITD circuit are MSO neurons with symmetric dendrites that segregate inputs from the ipsilateral and contralateral ears and preferential distribution of glycinergic inputs on MSO cell bodies. This circuit for ITD is well characterized in gerbils, a mammal with a prominent MSO and a low-frequency hearing range similar to humans. However, the organization of this circuit in the human MSO has not been characterized. This is further complicated by limited understanding of the human LNTB. Nonetheless, we hypothesized that the ITD circuit characterized in laboratory animals is similarly arranged in the human MSO. Herein, we utilized neuron reconstructions and immunohistochemistry to investigate the distribution of glutamatergic and glycinergic inputs onto human MSO neurons. Our results indicate that human MSO neurons have simple, symmetric dendrites and that glycinergic inputs outnumber glutamatergic inputs on MSO cell bodies and proximal dendrites. Together these results suggest that the human MSO utilizes similar circuitry to other mammals with excellent low-frequency hearing

Yes, there is a medial nucleus of the trapezoid body in humans

The medial nucleus of the trapezoid body (MNTB) is a collection of brainstem neurons that function within the ascending auditory pathway. MNTB neurons are associated with a number of anatomical and physiological specializations which make these cells especially well-equipped to provide extremely fast and precise glycinergic inhibition to its target neurons in the superior olivary complex and ventral nucleus of the lateral lemniscus. The inhibitory influence of MNTB neurons plays essentials roles in the localization of sound sources and encoding temporal features of complex sounds. The morphology, afferent and efferent connections and physiological response properties of MNTB neurons have been well-characterized in a number of laboratory rodents and some carnivores. Furthermore, the MNTB has been positively identified in all mammals examined, ranging from opossum and mice to chimpanzees. From the early 1970s through 2009, a number of studies denied the existence of the MNTB in humans and consequentially, the existence of this nucleus in the human brain has been debated for nearly 50 years. The absence of the MNTB from the human brain would negate current principles of sound localization and would require a number of novel adaptations, entirely unique to humans. However, a number of recent studies of human post-mortem tissue have provided evidence supporting the existence of the MNTB in humans. It therefore seems timely to review the structure and function of the MNTB, critically review the literature which led to the denial of the human MNTB and then review recent investigations supporting the existence of the MNTB in the human brain

Air pollution and detrimental effects on children's brain. The need for a multidisciplinary approach to the issue complexity and challenges

Millions of children in polluted cities are showing brain detrimental effects. Urban children exhibit brain structural and volumetric abnormalities, systemic inflammation, olfactory, auditory, vestibular and cognitive deficits v low-pollution controls. Neuroinflammation and blood-brain-barrier (BBB) breakdown target the olfactory bulb, prefrontal cortex and brainstem, but are diffusely present throughout the brain. Urban adolescent Apolipoprotein E4 carriers significantly accelerate Alzheimer pathology. Neurocognitive effects of air pollution are substantial, apparent across all populations, and potentially clinically relevant as early evidence of evolving neurodegenerative changes. The diffuse nature of the neuroinflammation and neurodegeneration forces to employ a weight of evidence approach incorporating current clinical, cognitive, neurophysiological, radiological and epidemiological research. Pediatric air pollution research requires extensive multidisciplinary collaborations to accomplish a critical goal: to protect exposed children through multidimensional interventions having both broad impact and reach. Protecting children and teens from neural effects of air pollution should be of pressing importance for public health

Sleep matters: Neurodegeneration spectrum heterogeneity, combustion and friction ultrafine particles, industrial nanoparticle pollution, and sleep disorders—Denial is not an option

Sustained exposures to ubiquitous outdoor/indoor fine particulate matter (PM2.5), including combustion and friction ultrafine PM (UFPM) and industrial nanoparticles (NPs) starting in utero, are linked to early pediatric and young adulthood aberrant neural protein accumulation, including hyperphosphorylated tau (p-tau), beta-amyloid (Aβ1 − 42), α-synuclein (α syn) and TAR DNA-binding protein 43 (TDP-43), hallmarks of Alzheimer's (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). UFPM from anthropogenic and natural sources and NPs enter the brain through the nasal/olfactory pathway, lung, gastrointestinal (GI) tract, skin, and placental barriers. On a global scale, the most important sources of outdoor UFPM are motor traffic emissions. This study focuses on the neuropathology heterogeneity and overlap of AD, PD, FTLD, and ALS in older adults, their similarities with the neuropathology of young, highly exposed urbanites, and their strong link with sleep disorders. Critical information includes how this UFPM and NPs cross all biological barriers, interact with brain soluble proteins and key organelles, and result in the oxidative, endoplasmic reticulum, and mitochondrial stress, neuroinflammation, DNA damage, protein aggregation and misfolding, and faulty complex protein quality control. The brain toxicity of UFPM and NPs makes them powerful candidates for early development and progression of fatal common neurodegenerative diseases, all having sleep disturbances. A detailed residential history, proximity to high-traffic roads, occupational histories, exposures to high-emission sources (i.e., factories, burning pits, forest fires, and airports), indoor PM sources (tobacco, wood burning in winter, cooking fumes, and microplastics in house dust), and consumption of industrial NPs, along with neurocognitive and neuropsychiatric histories, are critical. Environmental pollution is a ubiquitous, early, and cumulative risk factor for neurodegeneration and sleep disorders. Prevention of deadly neurological diseases associated with air pollution should be a public health priority

Noradrenergic axons hitch hiking along the human abducens nerve

The abducens nerve (AN; cranial nerve VI) exits the brainstem at the inferior pontine sulcus, pierces the dura of the posterior cranial fossa, passes through the cavernous sinus in close contact to the internal carotid artery (ICA) and traverses the superior orbital fissure to reach the orbit to innervate the lateral rectus muscle. At its exit from the brainstem, the AN includes only axons from lower motor neurons in the abducens nucleus. However, as the AN crosses the ICA it receives a number of branches from the internal carotid sympathetic plexus. The arrangement, neurochemical profile and function of these sympathetic axons running along the AN remain unresolved. Herein, we use gross dissection and microscopic study of hematoxylin and eosin-stained sections and sections with tyrosine hydroxylase immunolabeling. Our results suggest the AN receives multiple bundles of unmyelinated axons that use norepinephrine as a neurotransmitter consistent with postganglionic sympathetic axons

Noradrenergic axons hitch hiking along the human abducens nerve

The abducens nerve (AN; cranial nerve VI) exits the brainstem at the inferior pontine sulcus, pierces the dura of the posterior cranial fossa, passes through the cavernous sinus in close contact to the internal carotid artery (ICA) and traverses the superior orbital fissure to reach the orbit to innervate the lateral rectus muscle. At its exit from the brainstem, the AN includes only axons from lower motor neurons in the abducens nucleus. However, as the AN crosses the ICA it receives a number of branches from the internal carotid sympathetic plexus. The arrangement, neurochemical profile and function of these sympathetic axons running along the AN remain unresolved. Herein, we use gross dissection and microscopic study of hematoxylin and eosin-stained sections and sections with tyrosine hydroxylase immunolabeling. Our results suggest the AN receives multiple bundles of unmyelinated axons that use norepinephrine as a neurotransmitter consistent with postganglionic sympathetic axons

Premature termination of the sympathetic chain

The sympathetic chain serves to distribute visceral efferents and afferents over the entire body. The sympathetic chain courses from the base of the skull to the coccyx and sends branches to distribute along spinal nerves and a number of visceral nerves that distribute to cardiac muscle, smooth muscle and glands. During dissection of the posterior abdominal wall, we identified a rare variation of the sympathetic chain. In this subject, the sympathetic chain failed to send gray rami to the L2-4 spinal nerves and terminated by joining the S1 anterior ramus. Such a variation has only been reported once in the literature in 1895. We provide both schematic and photographic documentation of this variation and propose a number of possible circuits whereby visceral axons can reach their target despite these anatomical barriers

Leveling up: a long-range olivary projection to the medial geniculate without collaterals to the central nucleus of the inferior colliculus in rats

The medial nucleus of the trapezoid body (MNTB) is one of the monaural cell groups situated within the superior olivary complex (SOC), a constellation of brainstem nuclei with numerous roles in hearing. Principal MNTB neurons are glycinergic and express the calcium-binding protein, calbindin (CB). The MNTB receives its main glutamatergic, excitatory input from the contralateral cochlear nucleus via the calyx of Held and converts this into glycinergic inhibition directed toward nuclei in the SOC and the ventral and intermediate nuclei of the lateral lemniscus (VNLL and INLL). Through this inhibition, the MNTB plays essential roles in localization of sound sources and encoding spectral and temporal features of sound. In rats, very few MNTB neurons project to the inferior colliculus. However, our recent study of SOC projections to the auditory thalamus revealed a substantial number of retrogradely labeled MNTB neurons. This observation led us to examine whether the rat MNTB provides a long-range projection to the medial geniculate body (MGB). We examined this possible projection using retrograde and anterograde tract tracing and immunohistochemistry for CB and the glycine receptor. Our results demonstrate a significant projection to the MGB from the ipsilateral MNTB that does not involve a collateral projection to the inferior colliculus

Abnormal vestibular brainstem structure and function in an animal model of autism spectrum disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes several key neuropathological changes and behavioral impairments. In utero exposure to the anti-epileptic valproic acid (VPA) increases risk of an ASD diagnosis in human subjects and timed in utero exposure to VPA is a clinically relevant animal model of ASD. Many human subjects with ASD have cerebellar hypoplasia, fewer Purkinje cells, difficulties with balance, ophthalmic dysfunction and abnormal responses to vestibular stimulation and such vestibular difficulties are likely under reported in ASD. We have recently shown that animals exposed to VPA in utero have fewer neurons in their auditory brainstem, reduced axonal projections to the auditory midbrain and thalamus, reduced expression of the calcium binding protein calbindin (CB) in the brainstem and cerebellum, smaller and occasionally ectopic cerebellar Purkinje cells and ataxia on several motor tasks. Based on these findings, we hypothesized that in utero VPA exposure similarly impacts structure and function of the vestibular brainstem. We investigated this hypothesis using quantitative morphometric analyses, immunohistochemistry for CB, a battery of vestibular challenges, recording of vestibular-evoked myogenic potentials and spontaneous eye movements. Our results indicate that VPA exposure results in fewer neurons in the vestibular nuclei, fewer CB-positive puncta, difficulty on certain motor tasks, longer latency VEMPs and significantly more horizontal eye movements. These findings indicate that the vestibular nuclei are impacted by in utero VPA exposure and provide a basis for further study of vestibular circuits in human cases of ASD