Smell's puzzling discrepancy: Gifted discrimination, yet pitiful identification

Mind &Language, Volume 35, Issue 1, Page 90-114, February 2020

Parallel Odor Processing by Two Anatomically Distinct Olfactory Bulb Target Structures

The olfactory cortex encompasses several anatomically distinct regions each hypothesized to provide differential representation and processing of specific odors. Studies exploring whether or not the diversity of olfactory bulb input to olfactory cortices has functional meaning, however, are lacking. Here we tested whether two anatomically major olfactory cortical structures, the olfactory tubercle (OT) and piriform cortex (PCX), differ in their neural representation and processing dynamics of a small set of diverse odors by performing in vivo extracellular recordings from the OT and PCX of anesthetized mice. We found a wealth of similarities between structures, including odor-evoked response magnitudes, breadth of odor tuning, and odor-evoked firing latencies. In contrast, only few differences between structures were found, including spontaneous activity rates and odor signal-to-noise ratios. These results suggest that despite major anatomical differences in innervation by olfactory bulb mitral/tufted cells, the basic features of odor representation and processing, at least within this limited odor set, are similar within the OT and PCX. We predict that the olfactory code follows a distributed processing stream in transmitting behaviorally and perceptually-relevant information from low-level stations

Neural and behavioral plasticity in olfactory sensory deprivation

The human brain has a remarkable ability to reorganize as a consequence of altered demands. This ability is particularly noticeable when studying the neural effects of complete sensory deprivation. Both structural and functional cerebral reorganization have repeatedly been demonstrated in individuals with sensory deprivation, most evident in cortical regions associated with the processing of the absent sensory modality. Furthermore, sensory deprivation has been linked to altered abilities in remaining sensory modalities, often of a compensatory character. Although anosmia, complete olfactory sensory deprivation, is our most common sensory deprivation, estimated to affect around 5 % of the population, the effects of anosmia on brain and behavior are still poorly understood. The overall aim of this thesis was to investigate how the human brain and behavior are affected by anosmia, with a focus on individuals with congenital (lifelong) sensory deprivation. Specifically, Study I and Study IV assessed potential behavioral and neural multisensory compensatory abilities whereas Study II and Study III assessed potential reorganization beyond the processing of specific stimuli; the latter by determining morphological and resting-state functional connectivity alterations. Integration of information from different sensory modalities leads to a more accurate perception of the world around us, given that our senses provide complementary information. Although an improved ability to extract multisensory information would be of particular relevance to individuals deprived of one sensory modality, multisensory integration has been sparsely studied in relation to sensory deprivation. In Study I, multisensory integration of audio-visual stimuli was assessed in individuals with anosmia using two different experimental tasks. First, individuals with anosmia were better than matched controls in detecting multisensory temporal asynchronies in a simultaneity judgement task. Second, individuals with congenital, but not acquired, anosmia demonstrated indications of an enhanced ability to utilize multisensory information in an object identification task with degraded stimuli. Based on these results, the neural correlates of audio-visual processing and integration were assessed in individuals with congenital anosmia in Study IV. Relative to matched normosmic individuals, individuals with congenital anosmia demonstrated increased activity in established multisensory regions when integrating degraded audio-visual stimuli; however, no compensatory cross-modal processing in olfactory regions was demonstrated. Together, Study I and IV suggest that complete olfactory sensory deprivation is linked to enhanced audio-visual integration performance that might be facilitated by increased processing in multisensory regions. In Study II, whole-brain gray matter morphology was assessed in individuals with congenital anosmia. Both increases and decreases in the orbitofrontal cortex, a region associated with olfaction and sometimes referred to as secondary olfactory cortex, were observed in individuals with congenital anosmia in relation to matched controls. However, in contrast to our expectations, no sensory deprivation-dependent effects were demonstrated in piriform cortex, a region commonly referred to as primary olfactory cortex. Furthermore, Study III revealed an absence of differences in resting-state functional connectivity between individuals withcongenital anosmia and normosmic individuals within the primary olfactory cortex (including piriform cortex) as well as between core olfactory processing regions. In conclusion, the studies presented within this thesis suggest the existence of a potential multisensory compensatory mechanism in individuals with anosmia, but demonstrate a striking lack of morphological and functional alterations in piriform (primary olfactory) cortex. These results demonstrate that complete olfactory deprivation is associated with a distinct neural and behavioral reorganization in some regions but also a clear lack of effects in other regions; the latter underline the clear differences between our senses and suggest that extrapolating from individual senses should be done cautiously

A neuromorphic model of olfactory processing and sparse coding in the Drosophila larva brain

Animal nervous systems are highly efficient in processing sensory input. The neuromorphic computing paradigm aims at the hardware implementation of neural network computations to support novel solutions for building brain-inspired computing systems. Here, we take inspiration from sensory processing in the nervous system of the fruit fly larva. With its strongly limited computational resources of <200 neurons and <1.000 synapses the larval olfactory pathway employs fundamental computations to transform broadly tuned receptor input at the periphery into an energy efficient sparse code in the central brain. We show how this approach allows us to achieve sparse coding and increased separability of stimulus patterns in a spiking neural network, validated with both software simulation and hardware emulation on mixed-signal real-time neuromorphic hardware. We verify that feedback inhibition is the central motif to support sparseness in the spatial domain, across the neuron population, while the combination of spike frequency adaptation and feedback inhibition determines sparseness in the temporal domain. Our experiments demonstrate that such small, biologically realistic neural networks, efficiently implemented on neuromorphic hardware, can achieve parallel processing and efficient encoding of sensory input at full temporal resolution

Gestational Valproate Alters BOLD Activation in Response to Complex Social and Primary Sensory Stimuli

Valproic acid (VPA) has been used clinically as an anticonvulsant medication during pregnancy; however, it poses a neurodevelopmental risk due to its high teratogenicity. We hypothesized that midgestational (GD) exposure to VPA will lead to lasting deficits in social behavior and the processing of social stimuli. To test this, animals were given a single IP injection of 600 mg/kg of VPA on GD 12.5. Starting on postnatal day 2 (PND2), animals were examined for physical and behavior abnormalities. Functional MRI studies were carried out after PND60. VPA and control animals were given vehicle or a central infusion of a V1a antagonist 90 minutes before imaging. During imaging sessions, rats were presented with a juvenile test male followed by a primary visual stimulus (2 Hz pulsed light) to examine the effects of prenatal VPA on neural processing. VPA rats showed greater increases in BOLD signal response to the social stimulus compared to controls in the temporal cortex, thalamus, midbrain and the hypothalamus. Blocking the V1a receptor reduced the BOLD response in VPA animals only. Neural responses to the visual stimulus, however, were lower in VPA animals. Blockade with the V1a antagonist did not revert this latter effect. Our data suggest that prenatal VPA affects the processing of social stimuli and perhaps social memory, partly through a mechanism that may involve vasopressin V1a neurotransmission

An object's smell in the multisensory brain : how our senses interact during olfactory object processing

Object perception is a remarkable and fundamental cognitive ability that allows us to interpret and interact with the world we are living in. In our everyday life, we constantly perceive objects–mostly without being aware of it and through several senses at the same time. Although it might seem that object perception is accomplished without any effort, the underlying neural mechanisms are anything but simple. How we perceive objects in the world surrounding us is the result of a complex interplay of our senses. The aim of the present thesis was to explore, by means of functional magnetic resonance imaging, how our senses interact when we perceive an object’s smell in a multisensory setting where the amount of sensory stimulation increases, as well as in a unisensory setting where we perceive an object’s smell in isolation. In Study I, we sought to determine whether and how multisensory object information influences the processing of olfactory object information in the posterior piriform cortex (PPC), a region linked to olfactory object encoding. In Study II, we then expanded our search for integration effects during multisensory object perception to the whole brain because previous research has demonstrated that multisensory integration is accomplished by a network of early sensory cortices and higher-order multisensory integration sites. We specifically aimed at determining whether there exist cortical regions that process multisensory object information independent of from which senses and from how many senses the information arises. In Study III, we then sought to unveil how our senses interact during olfactory object perception in a unisensory setting. Other previous studies have shown that even in such unisensory settings, olfactory object processing is not exclusively accomplished by regions within the olfactory system but instead engages a more widespread network of brain regions, such as regions belonging to the visual system. We aimed at determining what this visual engagement represents. That is, whether areas of the brain that are principally concerned with processing visual object information also hold neural representations of olfactory object information, and if so, whether these representations are similar for smells and pictures of the same objects. In Study I we demonstrated that assisting inputs from our senses of vision and hearing increase the processing of olfactory object information in the PPC, and that the more assisting input we receive the more the processing is enhanced. As this enhancement occurred only for matching inputs, it likely reflects integration of multisensory object information. Study II provided evidence for convergence of multisensory object information in form of a non-linear response enhancement in the inferior parietal cortex: activation increased for bimodal compared to unimodal stimulation, and increased even further for trimodal compared to bimodal stimulation. As this multisensory response enhancement occurred independent of the congruency of the incoming signals, it likely reflects a process of relating the incoming sensory information streams to each other. Finally, Study III revealed that regions of the ventral visual object stream are engaged in recognition of an object’s smell and represent olfactory object information in form of distinct neural activation patterns. While the visual system encodes information about both visual and olfactory objects, it appears to keep information from the two sensory modalities separate by representing smells and pictures of objects differently. Taken together, the studies included in this thesis reveal that olfactory object perception is a multisensory process that engages a widespread network of early sensory as well higher-order cortical regions, even if we do not encounter ourselves in a multisensory setting but exclusively perceive an object’s smell

Valence, Arousal, and Gender Effect on Olfactory Cortical Network Connectivity: a study using Dynamic Causal Modeling for EEG

The cortical network including the piriform (PC), orbitofrontal (OFC), and entorhinal (EC) cortices allows the complex processing of behavioral, cognitive, and context-related odor information and represents an access gate to the subcortical limbic regions. Among the several factors that influence odor processing, their hedonic content and gender differences play a relevant role. Here, we investigated how these factors influence EEG effective connectivity among the mentioned brain regions during emotional olfactory stimuli. To this aim, we acquired EEG data from twenty-one healthy volunteers, during a passive odor task of odorants with different valence. We used Dynamic Causal Modeling (DCM) for EEG and Parametric Empirical Bayes (PEB) to investigate the modulatory effects of odors’ valence on the connectivity strengths of the PC-EC-OFC network. Moreover, we controlled for the influence of arousal and gender on such modulatory effects. Our results highlighted the relevant role of the forward and backward PC-EC connections in odor’s brain processing. On the one hand, the EC-to-PC connection was inhibited by both pleasant and unpleasant odors, but not by the neutral one. On the other hand, the PC-to-EC forward connection was found to be modulated (posterior probability (Pp)&gt;0.95) by the arousal level associated with an unpleasant odor. Finally, the whole network dynamics showed several significant gender-related differences (Pp&gt;0.95) suggesting a better ability in odor discrimination for the female gender

Cortical-hippocampal processing: prefrontal-hippocampal contributions to the spatiotemporal relationship of events

The hippocampus and prefrontal cortex play distinct roles in the generation and retrieval of episodic memory. The hippocampus is crucial for binding inputs across behavioral timescales, whereas the prefrontal cortex is found to influence retrieval. Spiking of hippocampal principal neurons contains environmental information, including information about the presence of specific objects and their spatial or temporal position relative to environmental and behavioral cues. Neural activity in the prefrontal cortex is found to map behavioral sequences that share commonalities in sensory input, movement, and reward valence. Here I conducted a series of four experiments to test the hypothesis that external inputs from cortex update cell assemblies that are organized within the hippocampus. I propose that cortical inputs coordinate with CA3 to rapidly integrate information at fine timescales. Extracellular tetrode recordings of neurons in the orbitofrontal cortex were performed in rats during a task where object valences were dictated by the spatial context in which they were located. Orbitofrontal ensembles, during object sampling, were found to organize all measured task elements in inverse rank relative to the rank previously observed in the hippocampus, whereby orbitofrontal ensembles displayed greater differentiation for object valence and its contextual identity than spatial position. Using the same task, a follow-up experiment assessed coordination between prefrontal and hippocampal networks by simultaneously recording medial prefrontal and hippocampal activity. The circuit was found to coordinate at theta frequencies, whereby hippocampal theta engaged prefrontal signals during contextual sampling, and the order of engagement reversed during object sampling. Two additional experiments investigated hippocampal temporal representations. First, hippocampal patterns were found to represent conjunctions of time and odor during a head-fixed delayed match-to-sample task. Lastly, I assessed the dependence of hippocampal firing patterns on intrinsic connectivity during the delay period versus active navigation of spatial routes, as rats performed a delayed-alternation T-maze. Stimulation of the ventral hippocampal commissure induced remapping of hippocampal activity during the delay period selectively. Despite temporal reorganization, different hippocampal populations emerged to predict temporal position. These results show hippocampal representations are guided by stable cortical signals, but also, coordination between cortical and intrinsic circuitry stabilizes flexible CA1 temporal representations

Circuit mechanisms for learning in the rodent Prefrontal cortex and their dysfunction in Schizophrenia

Flexible behavior, as shown by most mammals, requires continuous decision making where appropriate actions must be chosen from an array of available actions based on our current goals and prior experience. The medial prefrontal cortex (mPFC) is essential for selecting such appropriate actions and inhibiting inappropriate ones. The prefrontal cortex is not a homogenous structure but rather an agglomeration of sub-areas, which sub serve different functions. For example, the anterior cingulate is required for effort-based decision-making while the orbitofrontal cortex is essential for value based decision-making. However, the outcome of a decision making process is selection of a singular behavioral action or learning a new association. Hence, it would be reasonable to hypothesize that this selection would be a product of the combined output of the various prefrontal areas and the interactions among them. Thus to understand the neurobiological substrates of decision making one needs to explore the prefrontal cortex at two different levels: 1. The internal microcircuit and neuronal networks within individual prefrontal areas, and 2. Functional interactions among the prefrontal areas. The broad goal of my thesis was to use both of these approaches to study the prefrontal cortex of a well-established model organism (mouse) which has a relatively simple behavioral repertoire yet is evolutionarily complex enough to generalize my findings to higher order animals. First, I focused my attention on the Prelimbic (PreL) and Infralimbic (IL) regions of the mouse medial prefrontal cortex (mPFC). These two areas have been studied most extensively among the rodent prefrontal areas. In several behavioral domains, the PreL and IL exert distinct and opposing, influences over behavior; in a PreL-Go/IL-NoGo manner. The most common examples of this complementary function are the expression and extinction of conditioned fear responses or drug seeking behavior. Furthermore, neuronal tuning studies have shown that the PreL neurons are tuned to the representation of goals in goal directed learning while the IL neurons appear to tune to alternative choices. I investigated how the PreL and IL cortices interact among each other to influence learning and selection of behavioral strategies. Such, interactions between IL and PreL or other prefrontal areas have not been studied in detail in the past with one notable exception. Research done by Ji and Neugebauer (2012) have shown that optogenetic activation of IL inhibits PreL pyramidal cells in vivo, implying an existence of feed-forward inhibition from the IL to PreL. I carried out selective chemogenetic silencing of PreL or IL during different sub phases of the Intra-dimension/ extra-dimension set shifting task (IEST) or trace learning and extinction to evaluate their individual contributions. My findings suggest that PreL promotes application of behavioral strategies or new learning corresponding to previously learnt associations while IL is required to learn alternative associations across different learning paradigms. Next, using viral mediated tracing techniques I show the existence of reciprocal layer5/6 derived IL↔PreL projections. Using selective unidirectional silencing/activation of these projections, I have shown that the ILPreL and PreLIL projections are required at different phases of learning. Unidirectional ILPreL projections are specifically required during IL mediated alternative learning (eg: extinction) and the PreL↔IL reciprocal projections are required +12-14h post learning to setup the role of IL in subsequent learning of alternative choices. Prefrontal cortex dysfunction has been identified as a key neurobiological correlate of cognitive deficits associated with many neuropsychiatric disorders like Schizophrenia, Attention deficit/Hyperactivity disorder etc. Exploring the dysfunction of defined prefrontal neuronal networks and circuits in rodent models of neuropsychiatric disorders can be a different approach towards understanding decision making. In the second part of the thesis, I explored the dysfunction in the Parvalbumin (PV) interneuron network in a mouse model of Schizophrenia. Parvalbumin interneurons have been shown to synchronize network activity, supporting different types of neuronal network oscillations, such as gamma and theta oscillation, ripple and spindle activity. Thereby, they play a significant role in the formation and consolidation of memories to support learning and behavior. Finally, dysfunction of the Parvalbumin interneuron system in the prefrontal cortex of human schizophrenia patients has emerged as a core substrate underlying the cognitive deficits in the disease. Thus, studying the dysfunction of the PV network in Schizophrenia not only provides a way to understanding their role in prefrontal function but also raise the possibility of developing a strategy to ameliorate the associated cognitive deficits. I first showed that the PV network in LgDel+/- animals fail to mature with respect to those of their wild type counterparts and remain stuck in an immature state, which is associated with altered neural synchrony in the gamma band and behavioral deficits. I further show that stimulation of the PreL PV neuron network within a specific window of treatment during early adulthood can rescue the dysfunctional PV network synchrony as well as behavioral deficits. In recent years, interactions between the hippocampus and prefrontal cortex (PFC) have emerged as key players in various cognitive and behavioral functions. Disruptions in hippocampal-prefrontal interactions have also been observed in psychiatric disease, most notably schizophrenia. I saw that long-term rescue of the PreL PV state and associated behavioral deficits in LgDel+/- mice can also be mediated through direct stimulation of the ventral hippocampal (vH) PV network. However if the rescue is targeted to PreL while preventing it in vH or vice versa, it fails to mediate any behavioral rescue in LgDel+/- mice. Thus suggesting that long-term rescue of the PV pathology and cognitive deficits in LgDel+/- animals requires a rescue of the entire hippocampal-prefrontal axis