Cognitive impairments in schizophrenia are associated with lower gamma oscillation power in the prefrontal cortex (PFC). Gamma power depends in part on excitatory drive to fast-spiking parvalbumin ...interneurons (PVIs). Excitatory drive to cortical neurons varies in strength, which could affect how these neurons regulate network oscillations. The authors investigated whether variability in excitatory synaptic strength across PVIs could contribute to lower prefrontal gamma power in schizophrenia.
In postmortem PFC from 20 matched pairs of comparison and schizophrenia subjects, levels of vesicular glutamate transporter 1 (VGlut1) and postsynaptic density 95 (PSD95) proteins were quantified to assess variability in excitatory synaptic strength across PVIs. A computational model network was then used to simulate how variability in excitatory synaptic strength across fast-spiking (a defining feature of PVIs) interneurons (FSIs) regulates gamma power.
The variability of VGlut1 and PSD95 levels at excitatory inputs across PVIs was larger in schizophrenia relative to comparison subjects. This alteration was not influenced by schizophrenia-associated comorbid factors, was not present in monkeys chronically exposed to antipsychotic medications, and was not present in calretinin interneurons. In the model network, variability in excitatory synaptic strength across FSIs regulated gamma power by affecting network synchrony. Finally, greater synaptic variability interacted synergistically with other synaptic alterations in schizophrenia (i.e., fewer excitatory inputs to FSIs and lower inhibitory strength from FSIs) to robustly reduce gamma power.
The study findings suggest that greater variability in excitatory synaptic strength across PVIs, in combination with other modest synaptic alterations in these neurons, can markedly lower PFC gamma power in schizophrenia.
Understanding how each of the many interneuron subtypes affects brain network activity is critical. In the mouse olfactory system, mitral cells (MCs) and tufted cells (TCs) comprise parallel pathways ...of olfactory bulb output that are thought to play distinct functional roles in odor coding. Here, in acute mouse olfactory bulb slices, we test how the two major classes of olfactory bulb interneurons differentially contribute to differences in MC versus TC response properties. We show that, whereas TCs respond to olfactory sensory neuron (OSN) stimulation with short latencies regardless of stimulation intensity, MC latencies correlate negatively with stimulation intensity. These differences between MCs and TCs are caused in part by weaker excitatory and stronger inhibitory currents onto MCs than onto TCs. These differences in inhibition between MCs and TCs are most pronounced during the first 150 ms after stimulation and are mediated by glomerular layer circuits. Therefore, blocking inhibition originating in the glomerular layer, but not granule-cell-mediated inhibition, reduces MC spike latency at weak stimulation intensities and distinct temporal patterns of odor-evoked responses in MCs and TCs emerge in part due to differences in glomerular-layer-mediated inhibition.
Olfactory bulb mitral and tufted cells display different odor-evoked responses and are thought to form parallel channels of olfactory bulb output. Therefore, determining the circuit-level causes that drive these differences is vital. Here, we find that longer-latency responses in mitral cells, compared with tufted cells, are due to weaker excitation and stronger glomerular-layer-mediated inhibition.
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.
Sensory processing deficits are increasingly recognized as core symptoms of autism spectrum disorders (ASDs). However the molecular and circuit mechanisms that lead to sensory deficits are unknown. ...We show that two molecularly disparate mouse models of autism display similar deficits in sensory-evoked responses in the mouse olfactory system. We find that both
- and
-deficient mice of both sexes exhibit reduced response amplitude and trial-to-trial reliability during repeated odor presentation. Mechanistically, we show that both mouse models have weaker and fewer synapses between olfactory sensory nerve (OSN) terminals and olfactory bulb tufted cells and weaker synapses between OSN terminals and inhibitory periglomerular cells. Consequently, deficits in sensory processing provide an excellent candidate phenotype for analysis in ASDs.
The genetics of autism spectrum disorder (ASD) are complex. How the many risk genes generate the similar sets of symptoms that define the disorder is unknown. In particular, little is understood about the functional consequences of these genetic alterations. Sensory processing deficits are important aspects of the ASD diagnosis and may be due to unreliable neural circuits. We show that two mouse models of autism,
- and
-deficient mice, display reduced odor-evoked response amplitudes and reliability. These data suggest that altered sensory-evoked responses may constitute a circuit phenotype in ASDs.
The two‐step task, avoidance, and OCD Geramita, Matthew A.; Yttri, Eric A.; Ahmari, Susanne E.
Journal of neuroscience research,
June 2020, 2020-Jun, 2020-06-00, 20200601, Letnik:
98, Številka:
6
Journal Article
Recenzirano
In this invited review, we argue for the need to determine whether appetitive and aversive behaviors, be they goal‐directed or habitual, share overlapping neural circuitry. To motivate our argument, ...we first summarize what is currently known about the neural circuits governing aversive and appetitive behaviors by focusing first on the three hypothesized phases of avoidance learning, and then on goal‐directed and habitual reward seeking. We then provide several reasons to believe that the neural circuits of appetitive and aversive instrumental behaviors are not completely overlapping. We next discuss an experimental strategy to determine the extent of overlap based on a new computational framework that improves the identification of goal‐directed and habitual actions regardless of valence. Finally, we discuss recent work in obsessive‐compulsive disorder that uses this computational framework to determine whether patients perform appetitive and aversive versions of the same task using the same behavioral strategies and neural circuits.
Patients with obsessive-compulsive disorder (OCD) display disrupted performance and abnormal lateral orbitofrontal cortex (LOFC) activity during reversal learning tasks. However, 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.
Sapap3 knockout (KO) mice were used as a model for OCD-relevant behaviors. Sapap3 KOs and control littermates were injected with a 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 (18 mg/kg, 4 weeks).
Baseline compulsive grooming and reversal learning impairments in KOs improved after fluoxetine treatment. In addition, KOs displayed distinct patterns of abnormal LOFC activity during grooming and reversal learning, both of which normalized after fluoxetine. Finally, reversal learning–associated neurons were distributed randomly among grooming-associated neurons (i.e., overlap is what would be expected by chance).
In OCD, LOFC is disrupted during both compulsive behaviors and reversal learning, but whether these behaviors share common neural underpinnings is unknown. We found that LOFC plays distinct 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.
Lateral inhibition between pairs of olfactory bulb (OB) mitral cells (MCs) and tufted cells (TCs) is linked to a variety of computations including gain control, decorrelation, and gamma-frequency ...synchronization. Differential effects of lateral inhibition onto MCs and TCs via distinct lateral inhibitory circuits are one of several recently described circuit-level differences between MCs and TCs that allow each to encode separate olfactory features in parallel. Here, using acute OB slices from mice, we tested whether lateral inhibition is affected by prior odor exposure and if these effects differ between MCs and TCs. We found that early postnatal odor exposure to the M72 glomerulus ligand acetophenone increased the strength of interglomerular lateral inhibition onto TCs, but not MCs, when the M72 glomerulus was stimulated. These increases were specific to exposure to M72 ligands because exposure to hexanal did not increase the strength of M72-mediated lateral inhibition. Therefore, early life experiences may be an important factor shaping TC odor responses.
Responses of olfactory (OB) bulb mitral cells (MCs) and tufted cells (TCs) are known to depend on prior odor exposure, yet the specific circuit mechanisms underlying these experience-dependent changes are unknown. Here, we show that odor exposure alters one particular circuit element, interglomerular lateral inhibition, which is known to be critical for a variety of OB computations. Early postnatal odor exposure to acetophenone, a ligand of M72 olfactory sensory neurons, increases the strength of M72-mediated lateral inhibition onto TCs, but not MCs, that project to nearby glomeruli. These findings add to a growing list of differences between MCs and TCs suggesting that that these two cell types play distinct roles in odor coding.
Gamma-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.
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.
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