A thalamo-centric neural signature for restructuring negative self-beliefs

Negative self-beliefs are a core feature of psychopathology. Despite this, we have a limited understanding of the brain mechanisms by which negative self-beliefs are cognitively restructured. Using a novel paradigm, we had participants use Socratic questioning techniques to restructure negative beliefs during ultra-high resolution 7-Tesla functional magnetic resonance imaging (UHF 7 T fMRI) scanning. Cognitive restructuring elicited prominent activation in a fronto-striato-thalamic circuit, including the mediodorsal thalamus (MD), a group of deep subcortical nuclei believed to synchronize and integrate prefrontal cortex activity, but which has seldom been directly examined with fMRI due to its small size. Increased activity was also identified in the medial prefrontal cortex (MPFC), a region consistently activated by internally focused mental processing, as well as in lateral prefrontal regions associated with regulating emotional reactivity. Using Dynamic Causal Modelling (DCM), evidence was found to support the MD as having a strong excitatory effect on the activity of regions within the broader network mediating cognitive restructuring. Moreover, the degree to which participants modulated MPFC-to-MD effective connectivity during cognitive restructuring predicted their individual tendency to engage in repetitive negative thinking. Our findings represent a major shift from a cortico-centric framework of cognition and provide important mechanistic insights into how the MD facilitates key processes in cognitive interventions for common psychiatric disorders. In addition to relaying integrative information across basal ganglia and the cortex, we propose a multifaceted role for the MD whose broad excitatory pathways act to increase synchrony between cortical regions to sustain complex mental representations, including the self.

Excitatory effect of biphasic kHz field stimulation on CA1 pyramidal neurons in slices

Background: Electrical stimulation in the kilohertz-frequency range has been successfully used for treatment of various neurological disorders. Nevertheless, the mechanisms underlying this stimulation are poorly understood. Objective: To study the effect of kilohertz-frequency electric fields on neuronal membrane biophysics we developed a reliable experimental method to measure responses of single neurons to kilohertz field stimulation in brain slice preparations. Methods: In the submerged brain slice pyramidal neurons of the CA1 subfield were recorded in the whole-cell configuration before, during and after stimulation with an external electric field at 2kHz, 5kHz or 10 kHz. Results: Reproducible excitatory changes in rheobase and spontaneous firing were elicited during kHz-field application at all stimulating frequencies. The rheobase only decreased and spontaneous firing either was initiated in silent neurons or became more intense in previously spontaneously active neurons. Response thresholds were higher at higher frequencies. Blockade of glutamatergic synaptic transmission did not alter the magnitude of responses. Inhibitory synaptic input was not changed by kilohertz field stimulation. Conclusion: kHz-frequency current applied in brain tissue has an excitatory effect on pyramidal neurons during stimulation. This effect is more prominent and occurs at a lower stimulus intensity at a frequency of 2kHz as compared to 5kHz and 10kHz.

Disrupted-in-Schizophrenia-1 is required for proper pyramidal cell-interneuron communication and network dynamics in the prefrontal cortex

We interrogated prefrontal circuit function in mice lacking Disrupted-in-schizophrenia-1 (Disc1-mutant mice), a risk factor for psychiatric disorders. Single-unit recordings in awake mice revealed reduced average firing rates of fast-spiking interneurons (INTs), including optogenetically identified parvalbumin-positive cells, and a lower proportion of INTs phase-coupled to ongoing gamma oscillations. Moreover, we observed decreased spike transmission efficacy at local pyramidal cell (PYR)-INT connections in vivo, suggesting a reduced excitatory effect of local glutamatergic inputs as a potential mechanism of lower INT rates. On the network level, impaired INT function resulted in altered activation of PYR assemblies: While assembly activations were observed equally often, the expression strength of individual assembly patterns was significantly higher in Disc1-mutant mice. Our data thus reveal a role of Disc1 in shaping the properties of prefrontal assembly patterns by setting prefrontal INT responsiveness to glutamatergic drive.

The Stimulatory Effects of Intracellular α-Synuclein on Synaptic Transmission Are Attenuated by 2-Octahydroisoquinolin-2(1H)-ylethanamine

α-Synuclein (αSyn) species can be detected in synaptic boutons, where they play a crucial role in the pathogenesis of Parkinson’s Disease (PD). However, the effects of intracellular αSyn species on synaptic transmission have not been thoroughly studied. Here, using patch-clamp recordings in hippocampal neurons, we report that αSyn oligomers (αSynO), intracellularly delivered through the patch electrode, produced a fast and potent effect on synaptic transmission, causing a substantial increase in the frequency, amplitude and transferred charge of spontaneous synaptic currents. We also found an increase in the frequency of miniature synaptic currents, suggesting an effect located at the presynaptic site of the synapsis. Furthermore, our in silico approximation using docking analysis and molecular dynamics simulations showed an interaction between a previously described small anti-amyloid beta (Aβ) molecule, termed M30 (2-octahydroisoquinolin-2(1H)-ylethanamine), with a central hydrophobic region of αSyn. In line with this finding, our empirical data aimed to obtain oligomerization states with thioflavin T (ThT) and Western blot (WB) indicated that M30 interfered with αSyn aggregation and decreased the formation of higher-molecular-weight species. Furthermore, the effect of αSynO on synaptic physiology was also antagonized by M30, resulting in a decrease in the frequency, amplitude, and charge transferred of synaptic currents. Overall, the present results show an excitatory effect of intracellular αSyn low molecular-weight species, not previously described, that are able to affect synaptic transmission, and the potential of a small neuroactive molecule to interfere with the aggregation process and the synaptic effect of αSyn, suggesting that M30 could be a potential therapeutic strategy for synucleinopathies.

Non-monotonic effects of GABAergic synaptic inputs on neuronal firing

GABA is canonically known as the principal inhibitory neurotransmitter in the nervous system, usually acting by hyper-polarizing membrane potential. However, GABAergic currents can also exhibit non-inhibitory effects, depending on the brain region, developmental stage or pathological condition. Here, we investigate the diverse effects of GABA on the firing rate of several single neuron models, using both analytical calculations and numerical simulations. We find that the relationship between GABAergic synaptic conductance and output firing rate exhibits three qualitatively different regimes as a function of GABA reversal potential, νGABA: monotonically decreasing for sufficiently low νGABA (inhibitory), monotonically increasing for νGABA above firing threshold (excitatory); and a non-monotonic region for intermediate values of νGABA. In the non-monotonic regime, small GABA conductances have an excitatory effect while large GABA conductances show an inhibitory effect. We provide a phase diagram of different GABAergic effects as a function of GABA reversal potential and glutamate conductance. We find that noisy inputs increase the range of νGABA for which the non-monotonic effect can be observed. We also construct a micro-circuit model of striatum to explain observed effects of GABAergic fast spiking interneurons on spiny projection neurons, including non-monotonicity, as well as the heterogeneity of the effects. Our work provides a mechanistic explanation of paradoxical effects of GABAergic synaptic inputs, with implications for understanding the effects of GABA in neural computation and development.

The output of interneurons in the primary visual cortex is best reflected by pre-synaptic activity, not somatic activity

Recent advances in 2-photon calcium-imaging in awake mice have made it possible to study the effect of different behavioural states on cortical circuitry. Many studies assume that somatic activity can be used as a measure for neuronal output. We set out to test the validity of this assumption by comparing somatic activity with the pre-synaptic activity of VIP (Vasoactive intestinal peptide)- and SST (Somatostatin)-positive interneurons in layer 2/3 of the primary visual cortex (V1). We used mice expressing genetically encoded calcium indicators in VIP/SST-interneurons across the whole cell (VIP/SST:GCaMP6f) or confined to pre-synapses (VIP/SST:SyGCaMP5). Mice were exposed to a full-field visual stimulation protocol consisting of 60-second-long presentations of moving Gabor gratings (0.04 cpd, 2 Hz) alternated by 30 seconds of grey screen. During imaging, mice were placed on an air-suspended Styrofoam ball, allowing them to run voluntarily. We compared neural activity during three 4-second time-windows: Before visual stimulation (−4 to 0 sec), during the initial onset (1 to 5 sec) and at the end of the stimulation (56 to 60 sec.). These were further compared while the mice were stationary and while they were voluntarily locomoting. Unlike VIP-somas, VIP-pre-synapses showed strong suppressive responses to the visual stimulus. Furthermore, VIP-somas were positively correlated with locomotion, whereas in VIP-synapses we observed a split between positive and negative correlations. In addition, a similar but weaker distinction was found between SST-somas and pre-synapses. The excitatory effect of locomotion in VIP-somas increased over the course of the visual stimulus but this property was only shared with the positively correlated VIP-pre-synapses. The remaining negatively correlated pre-synapses showed no relation to the overall activity of the Soma. Our results suggest that when making statements about the involvement of interneurons in V1 layer 2/3 circuitry it is crucial to measure from synaptic terminals as well as from somas.

Modelling the spatial and temporal constrains of the GABAergic influence on neuronal excitability

GABA (γ-amino butyric acid) is an inhibitory neurotransmitter in the adult brain that can mediate depolarizing responses during development or after neuropathological insults. Under which conditions GABAergic membrane depolarizations are sufficient to impose excitatory effects is hard to predict, as shunting inhibition and GABAergic effects on spatiotemporal filtering of excitatory inputs must be considered. To evaluate at which reversal potential a net excitatory effect was imposed by GABA (EGABAThr), we performed a detailed in-silico study using simple neuronal topologies and distinct spatiotemporal relations between GABAergic and glutamatergic inputs. These simulations revealed for GABAergic synapses located at the soma an EGABAThr close to action potential threshold (EAPThr), while with increasing dendritic distance EGABAThr shifted to positive values. The impact of GABA on AMPA-mediated inputs revealed a complex temporal and spatial dependency. EGABAThr depends on the temporal relation between GABA and AMPA inputs, with a striking negative shift in EGABAThr for AMPA inputs appearing after the GABA input. The spatial dependency between GABA and AMPA inputs revealed a complex profile, with EGABAThr being shifted to values negative to EAPThr for AMPA synapses located proximally to the GABA input, while for distally located AMPA synapses the dendritic distance had only a minor effect on EGABAThr. For tonic GABAergic conductances EGABAThr was negative to EAPThr over a wide range of gGABAtonic values. In summary, these results demonstrate that for several physiologically relevant situations EGABAThr is negative to EAPThr, suggesting that depolarizing GABAergic responses can mediate excitatory effects even if EGABA did not reach EAPThr.

A thalamo-centric neural signature for restructuring negative self-beliefs

Negative self-beliefs are a core feature of psychopathology. Despite this, we have a limited understanding of the brain mechanisms by which negative self-beliefs are cognitively restructured. Using a novel paradigm, we had participants use Socratic questioning techniques to restructure self-beliefs during ultra-high resolution 7-Tesla functional magnetic resonance imaging (UHF fMRI) scanning. Cognitive restructuring elicited prominent activation in a fronto-striato-thalamic circuit, including the mediodorsal thalamus (MD), a group of deep subcortical nuclei believed to synchronize and integrate prefrontal cortex activity, but which has seldom been directly examined with fMRI due to its small size. Increased activity was also identified in the medial prefrontal cortex (MPFC), a region consistently activated by internally focused mental processing, as well as in lateral prefrontal regions associated with regulating emotional reactivity. Using Dynamic Causal Modelling (DCM), evidence was found to support the MD as having a strong excitatory effect on the activity of regions within the broader network mediating cognitive restructuring. Moreover, the degree to which participants modulated MPFC-to-MD effective connectivity during cognitive restructuring predicted their individual tendency to engage in repetitive negative thinking. Our findings represent a major shift from a cortico-centric framework of cognition and provide important mechanistic insights into how the MD facilitates key processes in cognitive interventions for common psychiatric disorders. In addition to relaying integrative information across basal ganglia and the cortex, we propose a multifaceted role for the MD whose broad excitatory pathways act to increase synchrony between cortical regions to sustain complex mental representations, including the self.

Separate and combined effects of cadmium(Cd) and nonylphenol(NP) on growth and antioxidative enzymes in Hydrocharis dubia (Bl.) Backer

Cadmium (Cd) is listed as a priority pollutant, and nonylphenol(NP) is a common organic pollutant in water environment. However, the ecological risks of combined pollution of Cd and NP have not been fully elucidated. In this study, the effects of Cd (0.01, 0.1, 0.5, 1, 5 mg/L), NP (0.1, 0.5, 1, 5, 10 mg/L) and Cd-NP (0.01 + 0.1, 0.01 + 1.0, 0.5 + 0.1, 0.5 + 1.0, 5 + 0.1, 5 + 1.0 mg/L) on growth and physiology of Hydrocharis Dubia (Bl.) Backer were studied. The results showed that the toxicity of H. dubia showed a dose-dependent effect. Growth level and chlorophyll contents of H. dubia induced by NP stress alone showed a certain toxicant excitatory effect. It meant that low concentrations of toxins promote plants growth, high concentrations of toxins inhibit plants growth. The increase of H2O2 content and the decrease of soluble protein content in the plant indicated that both Cd and NP caused oxidative damage to H. dubia. Under the stress, the antioxidant defense systems were activated, the activity of superoxide dismutase (SOD) was significantly decreased. The activity of catalase (CAT) reacted negatively under stress alone, but increased significantly under combined stress. The activity of peroxidase (POD) increased, which was used to alleviate the damage caused by toxics stress. The joint toxicity evaluation showed that the joint toxicity of Cd and NP to H. dubia was antagonistic when the concentrations of Cd + NP were 0.01 + 0.1 mg/L and 0.01 + 1 mg/L. At 0.5 + 0.1 mg/L and 0.5 + 1 mg/L, Cd and NP had a strong synergistic effect on H. dubia.