The Untouchable Ventral Nucleus of the Trapezoid Body: Preservation of a Nucleus in an Animal Model of Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by repetitive behaviors, poor social skills, and difficulties with communication and hearing. The hearing deficits in ASD range from deafness to extreme sensitivity to routine environmental sounds. Previous research from our lab has shown drastic hypoplasia in the superior olivary complex (SOC) in both human cases of ASD and in an animal model of autism. However, in our study of the human SOC, we failed to find any changes in the total number of neurons in the ventral nucleus of the trapezoid body (VNTB) or any changes in cell body size or shape. Similarly, in animals prenatally exposed to the antiepileptic valproic acid (VPA), we failed to find any changes in the total number, size or shape of VNTB neurons. Based on these findings, we hypothesized that the neurotransmitter profiles, ascending and descending axonal projections of the VNTB are also preserved in these neurodevelopmental conditions. We investigated this hypothesis using a combination of immunohistochemistry and retrograde tract tracing. We found no difference between control and VPA-exposed animals in the number of VNTB neurons immunoreactive for choline acetyltransferase (ChAT). Additionally, we investigated the ascending projections from the VNTB to both the central nucleus of the inferior colliculus (CNIC) and medial geniculate (MG) and descending projections to the cochlea. Our results indicate no significant differences in the ascending and descending projections from the VNTB between control and VPA-exposed animals despite drastic changes in these projections from surrounding nuclei. These findings provide evidence that certain neuronal populations and circuits may be protected against the effects of neurodevelopmental disorders.

When and How Does the Auditory Cortex Influence Subcortical Auditory Structures? New Insights About the Roles of Descending Cortical Projections

For decades, the corticofugal descending projections have been anatomically well described but their functional role remains a puzzling question. In this review, we will first describe the contributions of neuronal networks in representing communication sounds in various types of degraded acoustic conditions from the cochlear nucleus to the primary and secondary auditory cortex. In such situations, the discrimination abilities of collicular and thalamic neurons are clearly better than those of cortical neurons although the latter remain very little affected by degraded acoustic conditions. Second, we will report the functional effects resulting from activating or inactivating corticofugal projections on functional properties of subcortical neurons. In general, modest effects have been observed in anesthetized and in awake, passively listening, animals. In contrast, in behavioral tasks including challenging conditions, behavioral performance was severely reduced by removing or transiently silencing the corticofugal descending projections. This suggests that the discriminative abilities of subcortical neurons may be sufficient in many acoustic situations. It is only in particularly challenging situations, either due to the task difficulties and/or to the degraded acoustic conditions that the corticofugal descending connections bring additional abilities. Here, we propose that it is both the top-down influences from the prefrontal cortex, and those from the neuromodulatory systems, which allow the cortical descending projections to impact behavioral performance in reshaping the functional circuitry of subcortical structures. We aim at proposing potential scenarios to explain how, and under which circumstances, these projections impact on subcortical processing and on behavioral responses.

Autonomic and respiratory components of orienting behaviors are mediated by descending pathways originating from the superior colliculus

The ability to discriminate competing, ecologically relevant stimuli, and initiate contextually appropriate behaviors, is a key brain function. Neurons in the deep superior colliculus (dSC) integrate multisensory inputs and activate descending projections to premotor pathways responsible for orienting and attention, which often involve adjustments to respiratory and cardiovascular parameters. However, the neural pathways that subserve physiological components of orienting are poorly understood. We report that orienting responses to optogenetic dSC stimulation are accompanied by short-latency autonomic, respiratory and electroencephalographic effects in conscious rats, closely mimicking those evoked by naturalistic alerting stimuli. Physiological responses occurred in the absence of detectable aversion or fear and persisted under urethane anesthesia, indicating independence from emotional stress. Moreover, autonomic responses were replicated by selective stimulation of dSC inputs to the medullary reticular formation, a major target of dSC motor efferents, This disynaptic pathway represent a likely substrate for autonomic components of orienting.

The lateral periaqueductal gray and its role in controlling predatory hunting and social defense.

Evasion from imminent threats and prey attack are opposite behavioral choices critical to survival. The lateral periaqueductal gray (LPAG) is a key player in these behaviors, it responds to social threats and prey hunting while also driving predatory attacks and active defense. Our results revealed that distinct neuronal populations in the LPAG drive prey hunting and evasion from social threats. We show that the LPAG provides a putative glutamatergic projection to the lateral hypothalamic area (LHA). LPAG > LHA pathway optogenetic inhibition impaired insect predation but did not alter escape/attack ratio during social defeat. The results suggest that the LPAG control over evasion to a social attack may be regarded as a stereotyped response depending probably on descending projections. Conversely, the LPAG control over predatory behavior involves an ascending pathway to the LHA that likely influences LHAGABA neurons driving predatory hunting and may provide an emotional drive for appetitive rewards.

Two Neural Networks for Laughter: A Tractography Study

Laughter is a complex motor behavior occurring in both emotional and nonemotional contexts. Here, we investigated whether the different functions of laughter are mediated by distinct networks and, if this is the case, which are the white matter tracts sustaining them. We performed a multifiber tractography investigation placing seeds in regions involved in laughter production, as identified by previous intracerebral electrical stimulation studies in humans: the pregenual anterior cingulate (pACC), ventral temporal pole (TPv), frontal operculum (FO), presupplementary motor cortex, and ventral striatum/nucleus accumbens (VS/NAcc). The primary motor cortex (M1) and two subcortical territories were also studied to trace the descending projections. Results provided evidence for the existence of two relatively distinct networks. A first network, including pACC, TPv, and VS/NAcc, is interconnected through the anterior cingulate bundle, the accumbofrontal tract, and the uncinate fasciculus, reaching the brainstem throughout the mamillo-tegmental tract. This network is likely involved in the production of emotional laughter. A second network, anchored to FO and M1, projects to the brainstem motor nuclei through the internal capsule. It is most likely the neural basis of nonemotional and conversational laughter. The two networks interact throughout the pre-SMA that is connected to both pACC and FO.

Reciprocal connectivity of the periaqueductal gray with the ponto-medullary respiratory network in rat

Synaptic activities of the periaqueductal gray (PAG) can modulate or appropriate the respiratory motor activities in the context of behavior and emotion via descending projections to nucleus retroambiguus. However, alternative anatomical pathways for the mediation of PAG-evoked respiratory modulation via core nuclei of the brainstem respiratory network remains only partially described. We injected the retrograde tracer Cholera toxin subunit B (CT-B) in the pontine Kölliker-Fuse nucleus (KFn, n=5), medullary Bötzinger (BötC, n=3) and pre-Bötzinger complexes (pre-BötC; n=3), and the caudal raphé nuclei (n=3), and quantified the ascending and descending connectivity of the PAG. CT-B injections in the KFn, pre-BötC, and caudal raphé, but not in the BötC, resulted in CT-B-labeled neurons that were predominantly located in the lateral and ventrolateral PAG columns. In turn, CT-B injections into the lateral and ventrolateral PAG columns (n=4) yield the highest numbers of CT-B-labeled neurons in the KFn and far fewer numbers of labeled neurons in the pre-BötC and caudal raphé. Analysis of the relative projection strength revealed that the KFn shares the densest reciprocal connectivity with the PAG (ventrolateral and lateral columns, in particular). Overall, our data imply that the PAG may engage a distributed respiratory rhythm and pattern generating network beyond the nucleus retroambiguus to mediate downstream modulation of breathing. However, the reciprocal connectivity of the KFn and PAG suggests specific roles for synaptic interaction between these two nuclei that are most likely related to the regulation of upper airway patency during vocalization or other volitional orofacial behaviors.HighlightsThe lateral and ventrolateral PAG project to the primary respiratory network.The Kölliker-Fuse nucleus shares the densest reciprocal connectivity with the PAG.The Bötzinger complex appears to have very little connectivity with the PAG.

The lateral periaqeductal gray and its role in controlling the opposite behavioral choices of predatory hunting and social defense

Evasion from imminent threats and prey attack are opposite behavioral choices critical to survival. Curiously, the lateral periaqueductal gray (LPAG) has been implicated in driving both responses. The LPAG responds to social threats and prey hunting while also drives predatory attacks and active defense. However, the LPAG neural mechanisms mediating these behaviors remain poorly defined. Here, we investigate how the LPAG mediates the choices of predatory hunting and evasion from a social threat. Pharmacogenetic inhibition in Fos DD-Cre mice of neurons responsive specifically to insect predation (IP) or social defeat (SD) revealed that distinct neuronal populations in the LPAG drive the prey hunting and evasion from social threats. We show that the LPAG provides massive glutamatergic projection to the lateral hypothalamic area (LHA). Optogenetic inhibition of the LPAG-LHA pathway impaired IP but did not alter escape/attack ratio during SD. We also found that pharmacogenetic inhibition of LHAGABA neurons impaired IP, but did not change evasion during SD. The results suggest that the LPAG control over evasion to a social attack may be regarded as a stereotyped response depending probably on glutamatergic descending projections. On the other hand, the LPAG control over predatory behavior involves an ascending glutamatergic pathway to the LHA that likely influences LHAGABA neurons driving predatory attack and prey consumption. The LPAG-LHA path supposedly provides an emotional drive for prey hunting and, of relevance, may conceivably have more widespread control on the motivational drive to seek other appetitive rewards.

Descending projections from thesubstantia nigra pars reticulatadifferentially control seizures

Three decades of studies have shown that inhibition of thesubstantia nigra pars reticulata(SNpr) attenuates seizures, yet the circuits mediating this effect remain obscure. SNpr projects to the deep and intermediate layers of the superior colliculus (DLSC) and the pedunculopontine nucleus (PPN), but the contributions of these projections are unknown. To address this gap, we optogenetically silenced cell bodies within SNpr, nigrotectal terminals within DLSC, and nigrotegmental terminals within PPN. Inhibition of cell bodies in SNpr suppressed generalized seizures evoked by pentylenetetrazole (PTZ), partial seizures evoked from the forebrain, absence seizures evoked by gamma-butyrolactone (GBL), and audiogenic seizures in genetically epilepsy-prone rats. Strikingly, these effects were fully recapitulated by silencing nigrotectal projections. By contrast, silencing nigrotegmental terminals reduced only absence seizures and exacerbated seizures evoked by PTZ. These data underscore the broad-spectrum anticonvulsant efficacy of this circuit, and demonstrate that specific efferent projection pathways differentially control different seizure types.

Descending motor circuitry required for NT-3 mediated locomotor recovery after spinal cord injury in mice

Locomotor function, mediated by lumbar neural circuitry, is modulated by descending spinal pathways. Spinal cord injury (SCI) interrupts descending projections and denervates lumbar motor neurons (MNs). We previously reported that retrogradely transported neurotrophin-3 (NT-3) to lumbar MNs attenuated SCI-induced lumbar MN dendritic atrophy and enabled functional recovery after a rostral thoracic contusion. Here we functionally dissected the role of descending neural pathways in response to NT-3-mediated recovery after a T9 contusive SCI in mice. We find that residual projections to lumbar MNs are required to produce leg movements after SCI. Next, we show that the spared descending propriospinal pathway, rather than other pathways (including the corticospinal, rubrospinal, serotonergic, and dopaminergic pathways), accounts for NT-3-enhanced recovery. Lastly, we show that NT-3 induced propriospino-MN circuit reorganization after the T9 contusion via promotion of dendritic regrowth rather than prevention of dendritic atrophy.

Multiple non-auditory cortical regions innervate the auditory midbrain

ABSTRACTOur perceptual experience of sound depends on the integration of multiple sensory and cognitive domains, but the networks sub-serving this integration are unclear. There are connections linking different cortical domains, however we do not know if there are also connections between multiple cortical domains and subcortical structures. Retrograde tracing in rats revealed that the inferior colliculus – the auditory midbrain - receives dense descending projections from not only the auditory cortex, but also the visual, somatosensory, motor, and prefrontal cortices. While all these descending connections are bilateral, those from sensory areas show a more pronounced ipsilateral dominance than those from motor and prefrontal cortices. Anterograde tracing from cortical areas identified by retrograde tracing, showed cortical fibres terminating in all three subdivisions of the inferior colliculus, targeting both inhibitory and excitatory neurons. These findings demonstrate that auditory perception is served by a network that includes extensive descending connections from sensory, behavioural, and executive cortices.