Biology subjects

Safavi, S.

Publications and source records attributed to Safavi, S..

10 recordsLinked to original sources

bioRxiv2026

Network Dynamics and State-Dependent Effects of Electrical Stimulation in Recurrent Excitatory-Inhibitory Populations

Deep Brain Stimulation (DBS) is an established clinical treatment for a variety of neurological disorders, including Parkinsons Disease where it has been shown to reduce motor symptoms as well as disrupt pathological beta oscillations in the basal ganglia. The mechanisms of action of DBS on the collective activity of neuronal circuits is not fully understood. We use a recurrently-connected excitatory-inhbitory network based on the Brunel network architecture that can produce activity in a variety of states. Using a model of DBS that can reproduce observed effects such as antidromic activation, local somatic suppression, and axonal activation, we characterize the effect of stimulation across the entire parameter space of the network. We show that the effects of stimulation are dependent on the baseline state of the network, with the level of beta suppression dependent on the level of inhibition and the external drive. Specifically, networks with higher inhibition and lower drive show greater disruption of beta oscillations. We further show that networks in different states are preferentially sensitive to different frequencies of stimulation, suggesting that alternative protocols to the clinically standard high-frequency stimulation may have therapeutic efficacy.

neuroscience↗

bioRxiv2024

A decision-theoretic model of multistability: perceptual switches as internal actions

Perceptual multistability has been studied for centuries using a diverse collection of approaches. Insights derived from this phenomenon range from core principles of information processing, such as perceptual inference, to high-level concerns, such as visual awareness. The dominant computational explanations of perceptual multistability are based on the Helmholtzian view of perception as inverse inference. However, these approaches struggle to account for the crucial role played by value, e.g., with percepts paired with reward dominating for longer periods than unpaired ones. In this study, we formulate perceptual multistability in terms of dynamic, value-based, choice, employing the formalism of a partially observable Markov decision process (POMDP). We use binocular rivalry as an example, considering different explicit and implicit sources of reward (and punishment) for each percept. The resulting values are time-dependent and influenced by novelty as a form of exploration. The solution of the POMDP is the optimal perceptual policy, and we show that this can replicate and explain several characteristics of binocular rivalry, ranging from classic hallmarks such as apparently spontaneous random switches with approximately gamma-distributed dominance periods to more subtle aspects such as the rich temporal dynamics of perceptual switching rates. Overall, our decision-theoretic perspective on perceptual multistability not only accounts for a wealth of unexplained data, but also opens up modern conceptions of internal reinforcement learning in service of understanding perceptual phenomena, and sensory processing more generally.

neuroscience↗

bioRxiv2023

Emergence of a senescent and inflammatory pulmonary CD4+ T cell population prior to lung allograft failure

Lung transplantation is a life-saving therapy for end-stage pulmonary disease, but its long-term outlook is poor due to a high incidence of chronic lung allograft dysfunction (CLAD). CLAD results from alloimmune-mediated progressive fibrosis and culminates in death or the need for re-transplantation after a median of 6 years. Existing immunosuppression fails to prevent CLAD, suggesting the existence of alloimmune pathways resistant to these drugs. Here, we used mass cytometry to identify cell populations enriched in the bronchoalveolar lavage (BAL) of patients with subsequent allograft dysfunction. We show that CD4+CD57+PD1+ T cells emerge in stable lung transplant recipients in the first year post-transplant, conferring heightened risks for CLAD and death or re-transplantation. CD4+CD57+PD1+ T cells display features of senescence and secrete inflammatory cytokines. Cellular indexing by transcriptomes and epitopes (CITE-Seq) on BAL CD4+ T cells revealed the existence of 2 oligoclonal CD57+ subsets with putative cytotoxic and follicular helper functions. Finally, we observed that CD4+CD57+PD1+ T cells are associated with lung allograft fibrosis in a mouse model and in human explanted CLAD lungs, where they localize near airway epithelium and B cells. Together, our findings reveal the existence of an inflammatory T cell population that predicts future lung allograft dysfunction and may represent a rational therapeutic target in lung transplant recipients.

immunology↗

bioRxiv2023

Signatures of criticality in efficient coding networks

The critical brain hypothesis states that the brain can benefit from operating close to a second-order phase transition. While it has been shown that several computational aspects of sensory information processing (e. g., sensitivity to input) are optimal in this regime, it is still unclear whether these computational benefits of criticality can be leveraged by neural systems performing behaviorally relevant computations. To address this question, we investigate signatures of criticality in networks optimized to perform efficient encoding of stimuli. We consider a spike-coding network of leaky integrate-and-fire neurons with synaptic transmission delays and input noise. Previously, it was shown that the performance of such networks varies non-monotonically with the noise amplitude. Interestingly, we find that in the vicinity of the optimal noise level for efficient coding, the network dynamics exhibits signatures of criticality, namely, the distribution of avalanche sizes follows a power law. When the noise amplitude is too low or too high for efficient coding, the network appears either super-critical or sub-critical, respectively. Our work suggests that two influential, and previously disparate theories of neural processing optimization - efficient coding, and criticality - may be intimately related.

neuroscience↗

bioRxiv2022

A microtubule associated protein is essential for malaria parasite transmission

Mature gametocytes of Plasmodium (P.) falciparum display a banana (falciform) shape conferred by a complex array of subpellicular microtubules (SPMT) associated to the inner membrane complex (IMC). Microtubule associated proteins (MAPs) define MT populations and modulate interaction to pellicular components. Several MAPs have been identified in Toxoplasma gondii and homologues can be found in the genome of Plasmodium species, but the function of these proteins for asexual and sexual development of malaria parasites is still unknown. Here we identified a novel subpellicular MAP, termed SPM3, that is conserved within the genus Plasmodium., especially within the Laverania subgenus, but absent in other Apicomplexa. Conditional knockdown and targeted gene disruption of Pfspm3 in P. falciparum cause severe morphological defects during gametocytogenesis leading to round, non-falciform gametocytes with an aberrant SPMT pattern. In contrast, Pbspm3 knockout in P. berghei, a species with round gametocytes, caused no defect in gametocytogenesis, but sporozoites displayed an aberrant motility and a dramatic defect in sporozoite invasion of salivary glands leading to a decreased efficiency in transmission. Electron microscopy revealed a dissociation of the SPMT from the IMC in Pbspm3 knockout parasites suggesting a function of SPM3 in anchoring MTs to the IMC. Overall, our results highlight SPM3 as a pellicular component with essential functions for malaria parasite transmission. IMPORTANCEA key structural feature driving the transition between different life cycle stages of the malaria parasite is the unique three membrane "pellicle", consisting of the parasite plasma membrane (PPM) and a double membrane structure underlying the PPM termed the "inner membrane complex" (IMC). Additionally, there are numerous linearly arranged intramembranous particles (IMPs) linked to the IMC, which likely link the IMC to the subpellicular microtubule cytoskeleton. Here we identify, localize and characterize a novel subpellicular microtubule associated protein unique to the genus Plasmodium (P.). The knockout of this protein in the human infecting P. falciparum species result in malformed gametocytes and aberrant microtubules. We confirmed the microtubule association in the P. berghei rodent malaria homologue and show that its knockout results in a perturbated microtubule architecture, aberrant sporozoite motility and decreased transmission efficiency.

molecular biology↗

bioRxiv2021

Characterization of apicomplexan amino acid transporters (ApiATs) in the malaria parasite Plasmodium falciparum

During the symptomatic human blood phase, malaria parasites replicate within red blood cells. Parasite proliferation relies on the uptake of nutrients, such as amino acids, from the host cell and the blood plasma, requiring transport across multiple membranes. Amino acids are delivered to the parasite through the parasite surrounding vacuolar compartment by specialized nutrient-permeable channels of the erythrocyte membrane and the parasitophorous vacuole membrane (PVM). However, further transport of amino acid across the parasite plasma membrane (PPM) is currently not well characterized. In this study, we focused on a family of Apicomplexan amino acid transporters (ApiATs) that comprises five members in Plasmodium falciparum. First, we localized four of the PfApiATs at the PPM using endogenous GFP-tagging. Next, we applied reverse genetic approaches to probe into their essentiality during asexual replication and gametocytogenesis. Upon inducible knockdown and targeted gene disruption a reduced asexual parasite proliferation was detected for PfApiAT2 and PfApiAT4. Functional inactivation of individual PfApiATs targeted in this study had no effect on gametocyte development. Our data suggest that individual PfApiATs are partially redundant during asexual in vitro proliferation and fully redundant during gametocytogenesis of P. falciparum parasites. IMPORTANCEMalaria parasites live and multiply inside cells. To facilitate their extremely fast intracellular proliferation they hijack and transform their host cells. This also requires the active uptake of nutrients, such as amino acids, from the host cell and the surrounding environment through various membranes that are the consequence of the parasites intracellular lifestyle. In this manuscript we focus on a family of putative amino acid transporters termed ApiAT. We show expression and localization of four transporters in the parasite plasma membrane of Plasmodium falciparum-infected erythrocytes that represent one interface of the pathogen to its host cell. We probed into the impact of functional inactivation of individual transporters on parasite growth in asexual and sexual blood stages of P. falciparum and reveal that only two of them show a modest but significant reduction in parasite proliferation but no impact on gametocytogenesis pointing towards redundancy within this transporter family.

molecular biology↗

bioRxiv2020

Uncovering the Organization of Neural Circuits with Generalized Phase Locking Analysis

Despite the considerable progress of in vivo neural recording techniques, inferring the biophysical mechanisms underlying large scale coordination of brain activity from neural data remains challenging. One obstacle is the difficulty to link high dimensional functional connectivity measures to mechanistic models of network activity. We address this issue by investigating spike-field coupling (SFC) measurements, which quantify the synchronization between, on the one hand, the action potentials produced by neurons, and on the other hand a mesoscopic "field" signals, reflecting subthreshold activities at possibly multiple recording sites. As the number of recording sites gets large, the amount of pairwise SFC measurements becomes overwhelmingly challenging to interpret. We develop Generalized Phase Locking Analysis (GPLA) as a dimensionality reduction of this multivariate SFC. GPLA describes the dominant coupling between field activity and neural ensembles across space and frequencies, thereby providing rich yet interpretable information. In particular, we show that GPLA features are biophysically interpretable when used in conjunction with appropriate network models, such that we can identify the influence of underlying circuit properties on these features. We demonstrate the statistical benefits and interpretability of this approach in various computational models and Utah array recordings. The results suggest that GPLA used jointly with biophysical modeling can help uncover the contribution of recurrent microcircuits to the spatio-temporal dynamics observed in multi-channel experimental recordings.

neuroscience↗

bioRxiv2020

Prefrontal state fluctuations control access to consciousness

Access of sensory information to consciousness is thought to be mediated through ignition of neural activity in the prefrontal cortex (PFC). Ignition occurs once activity elicited by sensory input crosses a threshold, which has been shown to depend on brain state fluctuations. However, the neural correlates of fluctuations and their interaction with the neural representations of conscious contents within the PFC remain largely unknown. To understand the role of prefrontal state fluctuations in conscious access, we combined multielectrode intracortical recordings with a no-report binocular rivalry (BR) paradigm that induces spontaneously-driven changes in conscious perception. During BR, antagonistic coupling of two prefrontal states, characterised by dominance of low frequency (1-9Hz) or beta (20-40Hz) local field potentials (LFP), reflect competition between two states of visual consciousness; perceptual update and stability, respectively. Low frequency perisynaptic bursts precede spontaneous transitions in conscious perception, signalling upcoming perceptual update of conscious content. We therefore show that it is a global cortical state that seems to drive internal switches, rather than the spiking activity of selective neuronal ensembles, which subsequently, only report the active percept. Beta band bursts were found to be correlated with periods of stable conscious perception, and selectively synchronised the neural ensemble coding for the consciously perceived stimulus. Similar ongoing fluctuations in the LFPs, with dynamics resembling the distribution of perceptual dominance periods during BR, dominated the prefrontal cortex during resting-state, thus pointing to their default, endogenous nature. Our results suggest that the two modes of conscious perception: perceptual update, and stability, can be associated with distinct prefrontal cortical states.

neuroscience↗

bioRxiv2020

Decoding the contents of consciousness from prefrontal ensembles

Multiple theories attribute to the primate prefrontal cortex a critical role in conscious perception. However, opposing views caution that prefrontal activity could reflect other cognitive variables during paradigms investigating consciousness, such as decision-making, monitoring and motor reports. To resolve this ongoing debate, we recorded from prefrontal ensembles of macaque monkeys during a no-report paradigm of binocular rivalry that instigates internally driven transitions in conscious perception. We could decode the contents of consciousness from prefrontal ensemble activity during binocular rivalry with an accuracy similar to when these stimuli were presented without competition. Oculomotor signals, used to infer conscious content, were not the only source of these representations since visual input could be significantly decoded when eye movements were suppressed. Our results suggest that the collective dynamics of prefrontal cortex populations reflect internally generated changes in the content of consciousness during multistable perception. One sentence summaryNeural correlates of conscious perception can be detected and perceptual contents can be reliably decoded from the spiking activity of prefrontal populations.

neuroscience↗

bioRxiv2017

Non-monotonic spatial structure of interneuronal correlations in prefrontal microcircuits

Correlated fluctuations of single neuron discharges, on a mesoscopic scale, decrease as a function of lateral distance in early sensory cortices, reflecting a rapid spatial decay of lateral connection probability and excitation. However, spatial periodicities in horizontal connectivity and associational input as well as an enhanced probability of lateral excitatory connections in the association cortex could theoretically result in non-monotonic correlation structures. Here we show such a spatially non-monotonic correlation structure, characterized by significantly positive long-range correlations, in the inferior convexity of the macaque prefrontal cortex. This functional connectivity kernel was more pronounced during wakefulness than anesthesia and could be largely attributed to the spatial pattern of correlated variability between functionally similar neurons during structured visual stimulation. These results suggest that the spatial decay of lateral functional connectivity is not a common organizational principle of neocortical microcircuits. A non-monotonic correlation structure could reflect a critical topological feature of prefrontal microcircuits, facilitating their role in integrative processes.\n\nSignificance statementThe spatial structure of correlated activity of neurons in lower-order visual areas has been shown to linearly decrease as a measure of distance. The shape of correlated variability is a defining feature of cortical microcircuits as it constrains the computational power and diversity of a region. We show here for the first time a non-monotonic spatial structure of functional connectivity in the pre-frontal cortex where distal interactions are just as strong as proximal interactions during visual engagement of functionally similar PFC neurons. Such a nonmonotonic structure of functional connectivity could have far-reaching consequences in rethinking the nature and the role of prefrontal microcircuits in various cognitive states.

neuroscience↗