Graduate School of Systemic Neurosciences - Digitale Hochschulschriften der LMU

Humans explore the world by moving in it, whether moving their whole body as during walking or driving a car, or moving their arm to explore the immediate environment.

During movement, self-motion cues arise from the sensorimotor system comprising vestibular, proprioceptive, visual and motor cues, which provide information about direction and speed of the movement.

Such cues allow the body to keep track of its location while it moves through space.

Sensorimotor signals providing self-motion information can therefore serve as a source for spatial processing in the brain.

This thesis is an inquiry into human brain systems of movement and motion processing in a number of different sensory and motor modalities using functional magnetic resonance imaging (fMRI).

By characterizing connections between these systems and the spatial representation system in the brain, this thesis investigated how humans understand space by moving through it.

In the first study of this thesis, the recollection networks of whole-body movement were explored.

Brain activation was measured during the retrieval of active and passive self-motion and retrieval of observing another person performing these tasks.

Primary sensorimotor areas dominated the recollection network of active movement, while higher association areas in parietal and mid-occipital cortex were recruited during the recollection of passive transport.

Common to both self-motion conditions were bilateral activations in the posterior medial temporal lobe (MTL). No MTL activations were observed during recollection of movement observation.

Considering that on a behavioral level, both active and passive self-motion provide sufficient information for spatial estimations, the common activation in MTL might represent the common physiological substrate for such estimations.

The second study investigated processing in the 'parahippocampal place area' (PPA), a region in the posterior MTL, during haptic exploration of spatial layout.

The PPA in known to respond strongly to visuo-spatial layout.

The study explored if this region is processing visuo-spatial layout specifically or spatial layout in general, independent from the encoding sensory modality.

In both a cohort of sighted and blind participants, activation patterns in PPA were measured while participants haptically explored the spatial layout of model scenes or the shape of information-matched objects.

Both in sighted and blind individuals, PPA activity was greater during layout exploration than during object-shape exploration.

While PPA activity in the sighted could also be caused by a transformation of haptic information into a mental visual image of the layout, two points speak against this:

Firstly, no increase in connectivity between the visual cortex and the PPA were observed, which would be expected if visual imagery took place.

Secondly, blind participates, who cannot resort to visual imagery, showed the same pattern of PPA activity.

Together, these results suggest that the PPA processes spatial layout information independent from the encoding modality.

The third and last study addressed error accumulation in motion processing on different levels of the visual system.

Using novel analysis methods of fMRI data, possible links between physiological properties in hMT+ and V1 and inter-individual differences in perceptual performance were explored.

A correlation between noise characteristics and performance score was found in hMT+ but not V1.

Better performance correlated with greater signal variability in hMT+.

Though neurophysiological variability is traditionally seen as detrimental for behavioral accuracy, the results of this thesis contribute to the increasing evidence which suggests the opposite:

that more efficient processing under certain circumstances can be related to more noise in neurophysiological signals.

In summary, the results of this doctoral thesis contribute to our current understanding of motion and movement processing in the brain and its interface with spatial processing networks.

The posterior MTL appears to be a key region for both self-motion and spatial processing.

The results further indicate that physiological characteristics on the level of category-specific processing but not primary encoding reflect behavioral judgments on motion.

This thesis also makes methodological contributions to the field of neuroimaging:

it was found that the analysis of signal variability is a good gauge for analysing inter-individual physiological differences, while superior head-movement correction techniques have to be developed before pattern classification can be used to this end.

The medial superior olive (MSO) is an auditory brainstem nucleus within the superior olivary complex. Its functional role for sound source localization has been thoroughly investigated (for review see Grothe et al., 2010). However, few quantita tive data about the morphology of these neuronal coincidence detectors are available and computational models incorporating detailed reconstructions do not exist. This leaves open questions about metric characteristics of the morphology of MSO neurons as well as about electrophysiological properties that can be discovered using detailed multicompartmental models: what are the passive parameters of the membrane? What is the axial resistivity? How do dendrites integrate synaptic events? Is the medial dendrite symmetric to the lateral dendrite with respect to integration of synaptic events?

This thesis has two main aspects: on the one hand, I examined the shape of a MSO neuron by developing and applying various morphological quantifications. On the other hand, I looked at the impact of morphology on basic electrophysiological properties and on characteristics of coincidence detection. As animal model I used Mongolian gerbils (Meriones unguiculatus) during the late phase of development between postnatal day 9 (P9) and 37 (P37). This period of time is of special interest, as it spans from just before hearing onset at P12 – P13 (Finck et al., 1972; Ryan et al., 1982; Smith and Kraus, 1987) to adulthood. I used single cell electroporation, microscopic reconstruction, and compartmentalization to extract anatomical parameters of MSO neurons, to quantitatively describe their morphology and development, and to establish multi-compartmental models.

I found that maturation of the morphology is completed around P27, when the MSO neurons are morphologically compact and cylinder-like. Dendritic arbors become less complex between P9 and P21 as the number of branch points, the total cell length, and the amount of cell membrane decrease. Dendritic radius increases until P27 and is likely to be the main source of the increase in cell volume. In addition, I showed that in more than 85% of all MSO neurons, the axonal origin is located at the soma.

I estimated the axial resistivity (80 Ω·cm) and the development of the resting conductance (total conductance during the state of resting potential) which reaches 3 mS/cm2 in adult gerbils. Applying these parameters, multi-compartmental models showed that medial versus lateral dendritic trees do not equally integrate comparable synaptic inputs. On average, latencies to peak and rise times of lateral stimulation are longer (12 μs and 5 μs, respectively) compared to medial stimulation. This is reflected in the fact that volume, surface area, and total cell length of the lateral dendritic trees are significantly more larger in comparison to the medial ones.

Simplified models of MSO neurons showed that dendrites improve coincidence detection (Agmon-Snir et al., 1998; Grau-Serrat et al., 2003; Dasika et al., 2007). Here, I confirmed these findings also for multi-compartmental models with biological realistic morphologies. However, the improvement of coincidence detection by dendrites decreases during early postnatal development.

Aside from recognizing and distinguishing sound patterns, the ability to localize sounds in the horizontal plane is an essential component of the mammalian auditory system. It facilitates approaching potential mating partners and allows avoiding predators.

The superior olivary complex (SOC) within the auditory brainstem is the first site of binaural interaction and its major projections and inputs are well investigated. The adult input pattern, however, is not set from the beginning but changes over the period of development.

Mammals including humans experience different stages and conditions of hearing during auditory development. The human brain for instance has to perform a transition after birth from the perception of sound waves transmitted in amniotic fluid to the perception of airborne sounds. Furthermore, small mammals like rodents, which are common model organisms for auditory research, perceive airborne sounds for the first time some days after birth, when

their ear canals open. The basic neuronal projections and the intrinsic properties of neurons, such as the expression of specific ion channels, are already established and adjusted in the SOC during the perinatal period of partial deafness. An additional refinement of inputs and further adaptations of intrinsic characteristics occur with the onset of hearing in response to the new acoustic environment. It is likely that with ongoing maturation well-established inputs within the sound localization network need these adaptations to balance anatomical changes

such as an increasing head size. In addition, short-term adjustments of synaptic inputs in the adult auditory system are equally necessary for a faithful representation of auditory space. A recent study suggests that these short-term adaptations are partially represented at the

auditory brainstem level.

The question of how intrinsic properties change during auditory development, to what extent auditory experience is involved in these changes and the functional implications of these changes on the sound localization circuitry is only partially answered. I used the hyperpolarization-activated and cyclic nucleotide-gated cation channels (HCN channels), which are a key determinant of the intrinsic properties of auditory brainstem neurons, as a target to study the influence of auditory experience on the intrinsic properties of neurons in the auditory brainstem.

Another important question still under discussion is how neurons in the auditory brainstem might fine-tune their firing behavior to cope optimally with an altered acoustic environment.

Recent data suggest that auditory processing is also affected by modulatory mechanisms at the brainstem level, which for instance change the input strength and thus alter the spike output of these neurons. One possible candidate is the metabotropic GABAB receptor (GABABR) which has been shown to be abundant in the adult auditory brainstem, although GABAergic projections are scarce in the mature auditory brainstem.

These questions were investigated by performing whole-cell patch-clamp recordings of SOC neurons from Mongolian gerbils at different developmental stages in the acute brain slice preparation. Specific currents and receptors were isolated using pharmacological means.

Immmunohistochemical results additionally supported physiological findings.

In the first study, I investigated the developmental regulation of HCN channels in the SOC

and their underlying depolarizing current Ih, which has been shown to regulate the excitability of neurons and to enhance the temporally precise analysis of binaural acoustic cues. I characterized the developmental changes of Ih in neurons of the lateral superior olive (LSO) and the medial nucleus of the trapezoid body (MNTB), which in the adult animals show different HCN subunit composition. I showed that right after hearing onset there was a strong

increase of Ih in the LSO and just a minor increase in the MNTB. In addition, the open probability of HCN channels was shifted towards more positive voltages in both nuclei and

the activation time constants accelerated during the first days of auditory experience. These results implicate that Ih is actively regulated by sensory input activity. I tested this hypothesis by inducing auditory deprivation which was achieved by surgically removing the cochlea in

gerbils before hearing onset. The effect was opposite in neurons of the MNTB and the LSO.

Whereas in LSO neurons auditory deprivation resulted in increased Ih amplitude, MNTB neurons displayed a moderate decrease in Ih. These results suggest that auditory experience differentially changes the amount of HCN channels dependent on the subunit composition or

possibly alters intracellular cAMP levels, thereby shifting the voltage dependence of Ih. This regulatory mechanism might thus maintain adequate excitability levels within the SOC.

A second study was carried out to investigate the role of GABABRs in the medial superior olive (MSO). Upon activation, these metabotropic receptors are known to decrease the release probability of neurotransmitters at the presynapse thereby altering excitatory and inhibitory currents at the postsynaptic site. Neurons in the MSO analyze interaural time differences (ITDs) by comparing the relative timing of the excitatory inputs from the two ears

using a coincidence mechanism. In addition, these neurons receive a precisely timed inhibitory input from each ear which shifts ITDs in the physiological relevant range. Since the major inhibitory input changes its transmitter type from mixed GABA/glycinergic to only glycinergic after hearing onset it was now interesting to examine the mediated effects of GABABRs, which have been shown to be abundant in the prehearing and adult MSO of gerbils. Furthermore, revealing the precise expression pattern of GABABRs and their influence on excitatory and inhibitory currents in the MSO during auditory development should provide further evidence of their functional relevance. Performing pharmacological experiments I could now demonstrate that the activation of GABABRs before hearing onset decreases the current of excitatory inputs stronger than that of inhibitory inputs whereas a switch is performed after hearing onset and inhibitory currents are stronger decreasedcompared to excitatory currents. In a similar way, also the expression pattern of GABABRs

changes before and after hearing onset as revealed by immunohistochemistry. Since the main inhibitory inputs to the adult MSO are purely glycinergic, it was commonly assumed that GABABRs occupy only a minor role in the mature auditory brainstem. Contradictory to this, it was possible to activate presynaptic GABABRs by synaptic stimulation even in adult animals and to observe a profound decrease of inhibitory current in MSO neurons. These results suggest GABAergic projections of yet unknown origin targeting the MSO. It is therefore quite likely that GABABRs modulate and possibly improve the localization of low frequency sounds

even in adult mammals.

Summarized, the outcome of this thesis contributes to a better understanding of the developmental adaptation in the auditory system and demonstrates that the orderly

specification of intrinsic properties within the SOC is dependent on auditory experience. Moreover, I show that even in mature animals the synaptic strength of MSO inputs can be modulated by synaptic GABA release. This should emphasize the importance of modulatory mechanisms and could be the basis for future studies concerning the field of sound localization.