We live in an environment characterized by a multitude of complex, diverse sounds. The ability to filter, select and understand specific sounds from this rich environment can impact learning, speech, and even our survival. Just imagine driving your car in heavy traffic while listening intently to a radio interview when, in the distance, you hear a siren. That sound will automatically and immediately cause you to focus on the road, ignore the sound emanating from the radio, and take aversive action if necessary.
The cues that enable us to function optimally in our noisy, often cacophonous, world are central to the exciting research that is being performed in the laboratory of Dr. Daniel Llano, an associate professor in the University of Illinois Department of Molecular and Integrative Physiology (MIP) and a full-time faculty member at the Beckman Institute. Dr. Llano, who is also an MD with a subspecialty in neurology, has a clinical appointment at Carle Foundation Hospital and cares for patients with age-related auditory dysfunction and cognitive disorders. Thus, his research and clinical responsibilities are intimately linked.
The central auditory system, outlined in the graphic illustration below, is composed of pathways that ascend from sensory neurons in the auditory nerve to a succession of other key processing centers in the brainstem, midbrain and thalamus, with termination in the auditory cortex. Traditionally the ascending pathway has been emphasized, but studies utilizing tracers have demonstrated that descending neural fibers (projections) from the auditory portion of the cerebral cortex to lower processing centers greatly outnumber ascending projections in the central auditory system.
The descending projections that contribute to this “top-down” organization are critical in the process of interpretation and modulation of complex sounds with diverse characteristics. These sounds may also occur simultaneously, thereby being superimposed upon each other. One of the largest top-down pathways is the corticocollicular pathway (CC), which extends from the auditory cortex to the inferior colliculus (IC). The IC, located in the midbrain, is regarded as a major integrative center as it receives ascending signals from the auditory brainstem in addition to extensive descending signal input from the auditory cortex (AC). Its architecture is complex, consisting of a lateral cortex, a dorsal cortex and a central nucleus, each with different cell types which exhibit a variety of electrophysiological, morphological and molecular characteristics. The corticocollicular neurons have been shown to tune (or adjust the sensitivity of) IC neurons for frequency, amplitude and duration.
The importance of top-down modulation of response properties of neurons in lower auditory centers and a special interest in the massive corticocollicular pathway has led Dr. Llano’s laboratory to study the anatomical and also the functional (molecular and circuit level) organization of these descending neural projections. Tools utilized for these studies include electrophysiologic recording instrumentation in addition to novel optical and molecular techniques.
The auditory cortex is located on the superior temporal gyrus in the temporal lobe, and studies have shown that almost all regions of it project to the IC located on the same side, as opposed to the other IC that is located on the opposite side. The AC is composed of six layers (see figure below), each with specific types of cells. Descending projections, whether they are corticothalamic or corticocollicular, for example, arise from layers 5 and 6 of the AC, and the cell morphology (configuration) differs in each layer. Layer 5 corticocollicular cells are large, pyramidal cells with a long apical dendrite (the cell structure that receives information) projecting toward layer 1 whereas layer 6 cells are smaller, have long, thin, densely branching dendrites and are oriented horizontally as opposed to the layer 5 cells.
Although the anatomy and the functional roles of the corticothalamic projections have been extensively studied and delineated, knowledge of the role of the corticocollicular projections is limited. Dr. Llano’s laboratory, however, is making significant strides in providing an understanding of this critical information pathway.
In a publication in Hearing Research in 2014, Drs. Llano, Stebbings and Lesicko summarized their research findings, utilizing mice as mammalian subjects, which clearly demonstrate the heterogeneity of the descending CC pathway. Some of the neural projections from the auditory cortex to the IC respect what is known as a tonotopic relationship, meaning that neurons in the auditory cortex that have sensitivity to tones of a given frequency or frequency range project onto neurons in
the IC that display the same frequency sensitivity. The AC, however, can modulate or shift the tuning functions of IC neurons toward the tuning functions of the AC source.The CC pathway can also decrease responses to sound by the IC neurons via frequency-specific inhibition. Specific local circuit interactions in the IC may be either stimulated or suppressed, representing another mechanism by which the AC modulates IC neurons. Some regions of the IC are characterized by the above- described tonotopic configuration, but the laboratory has discovered other projections that are nontonotopic. Dr. Llano and his staff postulate that the tonotopically arranged projections from the AC can support frequency sensitivity adjustments (stimulatory or inhibitory) of neurons in the IC (i.e. “tuning”), but that perhaps the nontonotopic projections might play a role in modulating duration or temporal tuning.
Dr. Llano’s laboratory has shown that the descending input to the IC is primarily derived from cortical layer
5 neurons, but a spatially distinct pathway derived from layer 6 neurons also exists. Interestingly, layer 5 corticothalamic neurons are very similar to layer 5 corticocollicular neurons and single layer 5 cells may actually branch to many subcortical regions. Of importance is the fact that these layer 5 cells also exhibit bursting and receive both local excitatory and inhibitory cortical inputs from near the cell body as well as from upper cortical layers, as opposed to the layer 6 cells, which are non-bursting and also differ in additional electrophysiological metrics. Layer 6 cells differ in additional electrophysical metrics too. The layer 6 CC cells are also very different from their corticothalamic counterparts. Thus, it is likely that each separate pathway emanating from levels 5 and 6 respectively play distinct roles in processing auditory information in the midbrain.
The Llano laboratory has further explored the microarchitecture of the IC, and some fascinating findings have resulted from this research. They have discovered, utilizing immunostaining techniques, that the lateral cortex (LC) of the IC receives information not only from auditory structures but also, in multiple processing streams, information from somatosensory structures. In addition, the lateral cortex and the dorsal cortex areas of the IC receive considerably more projections from the auditory cortex than the central nucleus of the IC. Modular areas in the LC, which stains positively for a variety of neurochemicals, in particular the inhibitory neurotransmitter GABA, exist as early as day 8 in the mouse, before the onset of hearing, and these modules receive somatosensory input which probably drives their formation. The LC also receives input from the visual cortex, basal ganglia, hypothalamus, and deep layers of the superior colliculus (SC). (The superior colliculi are paired structures which play an important role in orienting eye and head movements to visual stimuli and in generating escape and defense behaviors.) Shared characteristics of cells in the SC and LC of the IC suggest related functional roles.
Therefore, multisensory integration (i.e., auditory, somatosensory and visual) occurs at each level of the ascending auditory pathway (cochlear nucleus, IC, medial geniculate body of the thalamus, and the auditory cortex).The findings that have emerged from Dr. Llano’s laboratory, however, have greatly enlarged our understanding of the multisensory connections to the descending CC pathway and, in his words, “will likely lead to broader insights about top-down modulatory pathways in general.”
For a deeper understanding of how the auditory cortex modulates the IC, the Llano laboratory has used optical stimulation and other sophisticated tools to study the integration of corticocollicular neurons in local cortical and corticothalamic networks. Previous studies have advanced the view that the thalamus provides input primarily to layer 4 of the cerebral cortex, but thalamocortical neurons also contact layers 5 and 6.The Llano laboratory has shown that layer 5 corticocollicular neurons receive prominent excitatory and inhibitory input from layer 5 to the pia (the innermost layer of the meninges which adheres to the surface of the brain and spinal cord) in a vertical fashion; however, layer 6 corticocollicular neurons receive inputs primarily from layer 6 in a horizontal orientation.
Neurons in layers 5 and 6 receive both direct and indirect thalamic input, but layer 5 corticocollicular neurons receive significantly more direct input from the auditory thalamus than layer 6 neurons. In fact, only a minority of layer 6 corticocollicular cells receive direct thalamic input.
An exciting result of this work is the demonstration, for the first time, that there is a direct connection between the auditory thalamus and layer 5 corticocollicular neurons, thereby linking the ascending and descending pathways. An understanding of the mechanisms that govern modulation of auditory information is emerging, pointing towards a duplex system which addresses issues of differing time scales, different degrees of convergence or divergence and different degrees of inhibition and excitation.
The concept of top-down modulation is key to our understanding of the auditory system. How do we process sounds? How do memories and previous experiences influence how we react to sounds? By studying top-down modulation might we understand the aging process better or even influence neuroprosthetic device design? These are just a few of the unanswered but critical questions that Dr. Llano’s laboratory is illuminating with truly innovative research.
