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Splitting sensory information into parallel pathways is a common strategy in sensory systems. Yet, how circuits in these parallel pathways are composed to maintain or even enhance the encoding of specific stimulus features is poorly understood. Here, we have investigated the parallel pathways formed by mitral and tufted cells of the olfactory system in mice and characterized the emergence of feature selectivity in these cell types via distinct lateral inhibitory circuits. We find differences in activity-dependent lateral inhibition between mitral and tufted cells that likely reflect newly described differences in the activation of deep and superficial granule cells. Simulations show that these circuit-level differences allow mitral and tufted cells to best discriminate odors in separate concentration ranges, indicating that segregating information about different ranges of stimulus intensity may be an important function of these parallel sensory pathways. The brain often processes different features of sensory information in separate pathways. For example, when seeing an object, information about colour and movement are processed by separate types of neurons in the eye. These neurons in turn relay information to different sets of brain areas, all of which are active at the same time. Such parallel processing was originally not thought to apply to information about smell. This was because in mammals, the two types of neurons in the brain area that processes smell seemed to play the same role. However, more recent work suggests that there are in fact differences in the responses of these two neuron types (called mitral cells and tufted cells) to odors, suggesting that the brain might use parallel processing for information about smells too. Information travels along neurons in the form of electrical signals, and this activity is often seen in the form of a series of “spikes”. In a process called lateral inhibition, the activity of one neuron can feed back and inhibit the activity of its neighbors. This is important for enhancing contrast; in terms of the sense of smell, lateral inhibition is thought to help distinguish between similar odors. A technique called optogenetics allows the activity of particular neurons in an animal’s brain to be controlled by shining light onto them. Geramita et al. have now used this technique in mice to investigate whether there are differences in how lateral inhibition works in mitral cells and tufted cells. This revealed that lateral inhibition affects mitral cells only when they are spiking at intermediate firing rates, whereas tufted cells are only affected by lateral inhibition when spiking at low firing rates. Using computer simulations, Geramita et al. show that these different responses mean that mitral cells are best at distinguishing similar smells when they are present at high concentrations, while tufted cells are best at distinguishing similar smells that are present at low concentrations. These differences also mean that, by working together, mitral and tufted cells can distinguish between smells much better than either type of neuron on its own. These results demonstrate that, as with the other senses, the brain processes information about smell using parallel pathways. Future work is now needed to see what effect switching off the activity of either mitral or tufted cells will have on an animal’s behavior.

Shiga toxin-producing Escherichia coli-associated haemolytic uraemic syndrome (STEC-HUS) is characterised by haemolytic anaemia, thrombocytopenia and acute kidney injury. Von Willebrand Factor (vWF) is an important mediator of normal thrombi formation and indirect evidence suggests that vWF may play an important role in Shiga toxin-induced thrombi formation. Clinical evidence supporting the role of vWF in STEC-HUS is lacking. A 10-year-old girl with type 1 von Willebrand Disease (vWD) had a mild case of STEC-HUS, with nadir haemoglobin 7.3 g/dL and platelet count 105×109 cells/L and peak serum creatinine 0.56 mg/L and lactate dehydrogenase 741 U/L. This is the first report of STEC-HUS in a patient with vWD. We speculate that the quantitative deficiency of vWF associated with type 1 vWD may have attenuated the course of disease by reducing platelet aggregation, complement activation and thrombi formation. This case adds to a growing literature supporting a link between vWF and STEC-HUS.

Splitting sensory information into parallel pathways is a common strategy in sensory systems. Yet, it is not well understood how circuits in these parallel pathways are composed to maintain or even enhance the encoding of specific stimulus features. In this dissertation, we investigate the parallel pathways formed by mitral and tufted cells (MCs and TCs) of the olfactory system and characterize the emergence of feature selectivity in these cell types via distinct patterns of connectivity to local inhibitory interneurons. Chapter 2 explores differences in feedforward circuitry onto MCs and TCs. We find that MCs display longer latency spiking that is more strongly dependent on stimulus intensity than TCs. Longer latency spiking in MCs is a consequence of weaker excitatory and stronger inhibitory currents, mediated by periglomerular cells, onto MCs compared to TCs. Chapter 3 describes the causes and consequences of lateral inhibition differences between MCs and TCs. We find that MCs are affected by lateral inhibition at intermediate firing rates, while TCs are affected at lower firing rates. These differences arise, in part, due to differential recruitment of morphologically distinct classes of granule cells by MCs and TCs. Using simulations, we show that these differences in lateral inhibition allow TCs and MCs to perform odor discriminations best in separate concentration ranges. Together, the experiments described here suggest that differences in odor-evoked responses between MCs and TCs are a consequence of distinct patterns of connectivity to multiple populations of inhibitory interneurons.

Determining the best possible action in an uncertain situation is often challenging, and organisms frequently need extra time to deliberate. This pause in behavior in response to uncertainty - also known as hesitation - commonly occurs in many aspects of daily life, yet its neural circuits are poorly understood. Here we present the first experimental paradigm that reliably evokes hesitation in mice. Using cell-type specific electrophysiology and optogenetics, we show that indirect, but not direct, pathway spiny projection neurons specifically in the dorsomedial striatum mediate hesitation. These data indicate that the basal ganglia circuits controlling the pausing involved in cognitive processes like hesitation are distinct from those that control other types of behavioral inhibition, such as cue-induced stopping.

Background: Patients with obsessive-compulsive disorder (OCD) display disrupted performance and abnormal lateral orbitofrontal cortex (LOFC) activity during reversal learning tasks, yet it is unknown whether compulsions and reversal learning deficits share a common neural substrate. To answer this question, we measured neural activity with in vivo calcium imaging in LOFC during compulsive grooming and reversal learning before and after fluoxetine treatment. Methods: Sapap3-knockout (KO) mice were used as a model for OCD-relevant behaviors. Sapap3-KOs and control littermates were injected with virus encoding GCaMP6f and implanted with gradient-index lenses to visualize LOFC activity using miniature microscopes. Grooming, reversal learning, and neural activity were measured pre- and post-fluoxetine treatment (18mg/kg, 4 weeks). Results: Baseline compulsive grooming and reversal learning impairments in KOs improved after fluoxetine treatment. Additionally, KOs display distinct patterns of abnormal LOFC activity during grooming and reversal learning, both of which normalize after fluoxetine. Finally, modulation in response to reversal learning and compulsive behavior are independent, as reversal learning-associated neurons are distributed randomly amongst grooming-associated neurons (i.e. overlap is what would be expected by chance). Conclusions: In OCD, the LOFC is disrupted during both compulsive behaviors and reversal learning, yet whether these behaviors share common neural underpinnings is unknown. We find that the LOFC plays distinct and independent roles in compulsive grooming and impaired reversal learning and their improvement with fluoxetine. These findings suggest that LOFC plays separate roles in pathophysiology and treatment of different perseverative behaviors in OCD. Competing Interest Statement The authors have declared no competing interest.

γ -Aminobutyric acid (GABA)-ergic transmission is critical for normal cortical function and is likely abnormal in a variety of neuropsychiatric disorders. We tested the in vivo effects of variations in two genes implicated in GABA function on GABA concentrations in prefrontal cortex of living subjects: glutamic acid decarboxylase 1 ( GAD1 ), which encodes GAD67, and catechol- o -methyltransferase ( COMT ), which regulates synaptic dopamine in the cortex. We studied six single nucleotide polymorphisms (SNPs) in GAD1 previously associated with risk for schizophrenia or cognitive dysfunction and the val158met polymorphism in COMT in 116 healthy volunteers using proton magnetic resonance spectroscopy. Two of the GAD1 SNPs (rs1978340 ( p =0.005) and rs769390 ( p =0.004)) showed effects on GABA levels as did COMT val158met ( p =0.04). We then tested three SNPs in GAD1 (rs1978340, rs11542313, and rs769390) for interaction with COMT val158met based on previous clinical results. In this model, rs11542313 and COMT val158met showed significant main effects ( p =0.001 and 0.003, respectively) and a trend toward a significant interaction ( p =0.05). Interestingly, GAD1 risk alleles for schizophrenia were associated with higher GABA/Cre, and Val-Val homozygotes had high GABA/Cre levels when on a GAD1 risk genotype background ( N =6). These results support the importance of genetic variation in GAD1 and COMT in regulating prefrontal cortical GABA function. The directionality of the effects, however, is inconsistent with earlier evidence of decreased GABA activity in schizophrenia.

The BDNF Val(66)Met polymorphism, a possible risk variant for mental disorders, is a potent modulator of neural plasticity in humans and has been linked to deficits in gray matter structure, function, and cognition. The impact of the variant on brain white matter structure, however, is controversial and remains poorly understood. Here, we used diffusion tensor imaging to examine the effects of BDNF Val(66)Met genotype on white matter microstructure in a sample of 85 healthy Caucasian adults. We demonstrate decreases of fractional anisotropy and widespread increases in radial diffusivity in Val/Val homozygotes compared with Met-allele carriers, particularly in prefrontal and occipital pathways. These data provide an independent confirmation of prior imaging genetics work, are consistent with complex effects of the BDNF Val(66)Met polymorphism on human brain structure, and may serve to generate hypotheses about variation in white matter microstructure in mental disorders associated with this variant.

The BDNF Val super(66)Met polymorphism, a possible risk variant for mental disorders, is a potent modulator of neural plasticity in humans and has been linked to deficits in gray matter structure, function, and cognition. The impact of the variant on brain white matter structure, however, is controversial and remains poorly understood. Here, we used diffusion tensor imaging to examine the effects of BDNF Val super(66)Met genotype on white matter microstructure in a sample of 85 healthy Caucasian adults. We demonstrate decreases of fractional anisotropy and widespread increases in radial diffusivity in Val/Val homozygotes compared with Met-allele carriers, particularly in prefrontal and occipital pathways. These data provide an independent confirmation of prior imaging genetics work, are consistent with complex effects of the BDNF Val super(66)Met polymorphism on human brain structure, and may serve to generate hypotheses about variation in white matter microstructure in mental disorders associated with this variant.

For decades, neurophysiologists have characterized the biophysical properties of a rich diversity of neuron types. However, identifying common features and computational roles shared across neuron types is made more difficult by inconsistent conventions for collecting and reporting biophysical data. Here, we leverage NeuroElectro, a literature-based database of electrophysiological properties (www.neuroelectro.org), to better understand neuronal diversity -- both within and across neuron types -- and the confounding influences of methodological variability. We show that experimental conditions (e.g., electrode types, recording temperatures, or animal age) can explain a substantial degree of the literature-reported biophysical variability observed within a neuron type. Critically, accounting for experimental metadata enables massive cross-study data normalization and reveals that electrophysiological data are far more reproducible across labs than previously appreciated. Using this normalized dataset, we find that neuron types throughout the brain cluster by biophysical properties into 6-9 super-classes. These classes include intuitive clusters, such as fast-spiking basket cells, as well as previously unrecognized clusters, including a novel class of cortical and olfactory bulb interneurons that exhibit persistent activity at theta-band frequencies.