Christiane Linster - US grants

Michael E. Hasselmo PROJECT SUMMARY Computer modeling techniques are required to understand how neurochemicals with subtle and broadly distributed effects alter brain function. In the proposed research, computer models of the olfactory system (the brain system for odor perception) will be used to aid in understanding the action of the neurochemicals acetylcholine and norepinephrine on the function of cells can affect the processing of odor memories. OBJECTIVES Research will focus on the following central questions: 1. How do the combined effects of noradrenaline and acetylcholine in the olfactory system affect the capacity of memory? Computer simulations will be used to model two components of the olfactory system: the olfactory bulb and olfactory cortex. Models will be used to analyze how modulation of inhibitory effects by acetylcholine and norepinephrine in the olfactory bulb and cortex increases the number of odor memories that can be stored by allowing them to be coded by separate populations of cells. 2. How does regulation of noradrenaline and acetylcholine in the olfactory system affect behavior in an odor learning task? Computer models will be used to analyze recent behavioral experiments in this laboratory testing how rats respond to odor pairs which share components (odor A with odor B, odor A with odor C) versus how they respond to odor pairs that do not share components (odor A with odor B, odor C with odor D). The model will generate predictions about how the response to odor pairs with shared components should differ depending on whether the response to odor pairs is based on the familiarity of the odor pair, or on whether the odor pair has been paired with a reward. 3. Does acetylcholine more strongly suppress spread of activity at synapses that have been recently increased in strength? Computer models show that storage of odor memories in the olfactory system appears to function more effectively when acetylcholine suppresses the spread of activity at recently strengthened synapses. This prevents recently stored memories from interfering with storage of new memories. In slices of olfactory cortex, we will test whether drugs that activate acetylcholine receptors more strongly suppress spread of activity at synapses which were recently strengthened by repetitive stimulation. 4. Computer models will be used to analyze the effect of acetylcholine and norepinephrine on fast and slow oscillations of activity in the olfactory system. The interaction of oscillations in the olfactory bulb and olfactory cortex will be analyzed, with an emphasis on feedback connections from the olfactory cortex back to the olfactory bulb.

DESCRIPTION (provided by applicant): Understanding the role of neuromodulators for cortical function requires the study of their effects at the level of neural responses, as well as at the level of behavioral responses. Theoretical models of olfactory processing, supported by behavioral lesion experiments, predict that cholinergic modulation in the olfactory system would serve to increase the discrimination between similar olfactory stimuli. In vivo extracellular recording techniques will be employed in this research project to test how the olfactory responses of cells in the olfactory bulb and cortex are modulated by cholinergic inputs. The molecular response spectra of mitral cells in the olfactory bulb and of pyramidal cells in the olfactory cortex are modulated by cholinergic inputs in such a way as to increase the discrimination of similar odorants by these cells. Extracellular recording techniques will be used in the olfactory bulb and cortex of anesthetized rats to analyze the degree of overlap in neural activity patterns in response to series of n-aliphatic aldehydes and n-fatty acids. Electrical stimulation of the horizontal limb of the diagonal band of Broca will be used to activate cholinergic projections to the olfactory bulb and cortex. The comparison of neural response profiles to odorants in the absence and in the presence of the stimulation of cholinergic fibers will serve to determine how changes in cholinergic modulation affect odor responses. The cholinergic nature of the observed effects will be tested by injection of cholinergic antagonists (muscarinic and/or nicotinic). The results from these experiments will help understand the processes underlying impairments in odor processing and learning observed in behavioral studies and will test predictions about the functional role of cholinergic modulation in sensory processing.

This proposal presents a multidisciplinary, collaborative approach to understanding a basic function of all neuronal sensory systems, namely, modification by experience and filtering of background or biologically irrelevant stimuli. The proposal specifically focuses on odor habituation in rat olfactory bulb and cortex. The olfactory system represents an ideal system for such studies for several reasons, each of which is taken advantage of by the proposed studies. First, the mammalian olfactory system is anatomically relatively simple, with the olfactory cortex one of the evolutionarily oldest mammalian sensory cortices. Second, this relative simplicity has resulted in extensive knowledge of synaptic connections and physiology of both afferent and intracortical fiber systems and their regulation by neuromodulatory systems. Third, this knowledge has allowed development of computational models which include both olfactory bulb and piriform cortical neurons. Specifically the project will determine the synaptic mehcnaisms of odor habituation and odor-specificity of habituation in cortical neurons and then incorporate the electrophysiological results into a computational model of the cortex which will be used to make and test predictions about odor habituation and stimulus-background segmentation in an odor environment.

The project combines the expertise of two active research groups specializing in sensory physiology and computational modeling. This research environment will be used to expose students, high school through graduate from diverse backgrounds to new research techniques and conceptual approaches.

[unreadable] DESCRIPTION (provided by applicant): This proposal presents a multidisciplinary approach to understanding a fundamental property of noradrenergic modulation in the mammalian brain: the non-linear action of the neuromodulator noradrenaline on cellular properties and the translation of these cellular effects into the modulation of sensory perception. The proposal addresses this question in the olfactory bulb of rats, using a combination of brain slice electrophysiology, behavioral pharmacology and computational modeling tools. The olfactory system represents an ideal system for such studies for several reasons, each of which is taken advantage of by the proposed studies. First, the mammalian olfactory system is anatomically relatively simple, and this simplicity has resulted in an extensive knowledge of synaptic connections and physiology and their regulation by neuromodulatory systems. Second, because olfactory bulb principal neurons are only a single synapse removed from primary olfactory sensory neurons, a relatively good understanding of the relationship between neural representations and perception of chemical signals has been developed. Third, this knowledge in turn has enabled the development of computational models which include the olfactory bulb and its neuromodulatory inputs. Finally, aided by the importance of olfaction to rats' survival, a variety of assays relying on these natural behaviors have been developed that can assess the effect of noradrenergic modulation on odor-guided behavior. It is specifically proposed to 1) determine the effects of increasing concentrations of the neuromodulator noradenaline on olfactory bulb mitral and granule cell properties, 2) test how the net concentration-dependence of noradrenergic effects is mediated by the different noradrenergic receptor subtypes and their binding affinities, 3) use a biophysical modeling approach to determine whether the cellular experimental data are sufficient to explain the overall network effects of noradrenaline, and 4) test functional predictions from these results using pharmacological manipulations during behavioral tests in rats. Taken together, the proposed experiments will elucidate how the nonlinear effects of noradrenergic modulation in sensory systems arise from the interaction with various receptor subtypes as well as how these nonlinear effects at the cellular level translate into perceptual modulation, and hence will have a broad impact on our understanding of sensory processing and neuromodulation. Neuromodulation is involved in many major degenerative diseases of brain function; a better understanding of the functions of these systems will have a high impact on public health. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Understanding the functional role of neuromodulation for sensory processing is a crucial step in understanding the impact of neurodegenerative diseases affecting neuromodulatory centers in the brain on sensory processing. The overall goal of this project is to further our understanding of the functional role of acetylcholine in olfactory sensation by recording from the neuromodulatory neurons projecting to the olfactory system during olfactory behaviors. I propose to characterize during which parts of olfactory sensation neurons emitting acetylcholine (ACh) to the olfactory system are activated. Together with data already collected on how the blockade of these substances locally in the OB affects olfactory behaviors, these data will be crucial to a more complete understanding of neuromodulatory function in the OB. These data should provide important insights into how neurodegenerative diseases affect olfactory sensation. [unreadable] [unreadable] [unreadable]

Description (provided by applicant): Neuromodulatory inputs to early sensory processing areas, such as acetylcholine, noradrenaline, serotonin and dopamine, are thought to support a number of functions relating attention, alert, reward and emotional states. Neuromodulatory inputs regulate the states of sensory and cortical networks, change local computations and affect the dynamics of these networks. Among early sensory processing areas, because of the strong correlations between sensory inputs, neural activity and perception, the transformation of sensory perception by neuromodulatory inputs is directly measurable in the olfactory bulb (OB) of rodents. A crucial function of the OB is to integrate afferent information from the sensory neurons in concert with descending cortical and neuromodulatory inputs from central structures such as the piriform cortex, basal forebrain and brain stem. Accumulating evidence indicates that olfactory discrimination is at least partially mediated by processes in the OB and that cholinergic as well as noradrenergic centrifugal inputs to the OB modulate perceptual discrimination. The present proposal uses multi-electrode recordings in behaving rats to further elucidate the contribution of cholinergic and noradrenergic inputs to the OB for olfactory perception and learning. Neural activity in the locus coeruleus and horizontal limb of the diagonal band of Boca will be recorded in rats performing one of three different olfactory tasks. We hypothesize that cholinergic inputs will be involved in shaping olfactory representations and comparisons of stimuli to those previously encoded whereas noradrenergic inputs will be involved in the formation and maintenance of short memoires as well as in the regulation of signal-to noise ratio. PUBLIC HEALTH RELEVANCE: Neuromodulatory inputs to primary sensory cortex modulate sensory perception and learning. Disruption of these processes leads to impairments in the detection, discrimination and learning of sensory inputs. The proposed work will have significance for our understanding of how neuromodulatory inputs are involved in sensory processing and memory formation.

Social interactions between all animals are a highly important function of mammalian brains. Limited or mal-functioning social interactions can have a high impact on an animal or person's life quality, life span, and reproductive success - examples include Autism, Personality disorders, Williams syndrome, Prenatal alcohol syndrome and others. During social interactions, specific neuro-hormones change sensory perception and cognitive processes in our brains to be adaptive and optimized to these specific tasks. The investigators propose a detailed investigation of the effects of one such substance, oxytocin, on social recognition and memory using an interdisciplinary approach in mice that combines state of the art experimental and computational approaches. The investigators study to what extend oxytocin changes computations in the brain during social interactions, the neural mechanisms through which oxytocin causes these changes. For example, a lack of oxytocin can limit an animal's social recognition capacity and memory and interfere with social structures in individuals and groups. Understanding systems that play a role in social interactions and recognition has a potential high impact on understanding and treating disorders of social interactions. The project also offers interdisciplinary (computational and neuro-biology) and international (USA and Germany) research opportunities for trainees at the undergraduate and postdoctoral level.

Behavioral context and demands can modulate brain state and neural computations via influx of neuromodulators and -hormones. This proposal studies the relationships between brain state, neural computation, and plasticity by taking advantage of a well-established model system. The neurohormone oxytocin is triggered during specific behavioral situations and supports neural plasticity and learning in those situations. Other neuromodulators, such as acetylcholine, noradrenaline, and serotonin released in response to behavioral contexts such as attention, stress, or hunger change how brain networks compute to best respond to these behavioral situations. Although there is extensive knowledge of cellular and network effects of these substances, knowledge about contexts in which these are released remains vague, and correlating the effects of neuromodulators with specific behavioral situations is difficult. Olfactory system modulation by oxytocin provides with a unique opportunity to directly ask how neural processing is modulated to enable more stable memories, what about neural representations is important for stable memories, and how feedback interactions between sensory, modulatory, and cortical areas interact during the formation and expression of these memories. This project specifically addresses how and through which (a) network and (b) cellular and synaptic mechanisms oxytocin changes the signal-to-noise ratio of odor representations in the olfactory bulb. The project also examines how the feedback loop between olfactory bulb and cortex enhances stable odor trajectories. To achieve these objectives, the investigators apply an interdisciplinary approach using state of the art experimental and computational techniques. A companion project is being funded by the Federal Ministry of Education and Research, Germany (BMBF).

Project Summary Sensory signals encountered under different circumstances may have quite different implications. In the early olfactory system, preliminary evidence suggests that this (non-olfactory) contextual information is integrated into odor representations at a very early stage, potentially even the main olfactory bulb. Recent evidence indicates that the anterior olfactory nucleus (AON), a structure directly adjoining the olfactory bulb, serves to integrate afferent odor information with contextual information from the ventral hippocampus (vHC) and is necessary to solve contextually-dependent olfactory decision-making tasks. The vHC is known to relay task-relevant spatial contextual information to other brain systems. We here hypothesize that direct projections from the vHC to the AON play a dominant role in the integration of contextual and olfactory information, and that the AON embeds this multisensory contextual information into early-stage odor representations. Our preliminary data show that rodents can learn to respond differently to odors based on the spatial context in which they are encountered, and that the expression of such a rule depends on both AON and vHC, whereas a similar but odor-independent task requires vHC but not AON. We propose a multipronged approach to understanding the integration of spatial context into olfactory representations, engaging electrophysiological ensemble recordings and interareal coherence measurements in awake, behaving rodents, the optogenetic manipulation of vHC and AON circuit activities, and a double-labeling strategy for the within-subjects comparison of immediate-early gene (Fos) responses across two experimental conditions separated in time.