Networks of excitatory and inhibitory (EI) neurons form a canonical circuit in the brain. Seminal theoretical results on the dynamics of such networks are based on the assumption that synaptic strengths depend on the type of neurons they connect, but are otherwise statistically independent. Recent synaptic physiology datasets, however, highlight the prominence of specific connectivity patterns that go well beyond what is expected from independent connections. While decades of influential research have demonstrated the strong role of the basic EI cell type structure, the extent to which additional connectivity features influence dynamics remains to be fully determined. Here we examine the effects of pairwise connectivity motifs on the linear dynamics in excitatory-inhibitory networks using an analytical framework that approximates the connectivity in terms of low-rank structures. This low-rank approximation is based on a mathematical derivation of the dominant eigenvalues of the connectivity matrix, and it predicts the impact on responses to external inputs of connectivity motifs and their interactions with cell-type structure. Our results reveal that a particular pattern of connectivity, namely chain motifs, have a much stronger impact on dominant eigenmodes than other pairwise motifs. In particular, an over-representation of chain motifs induces a strong positive eigenvalue in inhibition-dominated networks, and it generates a potential instability that requires revisiting the classical excitation-inhibition balance criteria. Examining the effects of external inputs, we show that chain motifs can on their own induce paradoxical responses, where an increased input to inhibitory neurons leads to a decrease in their activity due to the recurrent feedback. These findings have direct implications for the interpretation of experiments in which responses to optogenetic perturbations are measured and used to infer the dynamical regime of cortical circuits.
Short Term Experiences in Global Health (STEGH) are becoming increasingly prevalent, where students and volunteers predominately from high income countries travel to lower income countries to work with local community organizations. Although the benefits of STEGHs have been touted, they have also been increasingly criticized as representing a new form of colonialism and have been shown to harm host communities in a number of ways. Can the enterprise of STEGHs be ethically justified? We argue that STEGHs must incorporate principles of bi-directionality, continuity, cultural humility and decolonization in order to be equitable and sustainable.
Authors rely on a range of devices and techniques to attract and maintain the interest of readers, and to convince them of the merits of the author’s point of view. However, when writing a scientific article, authors must use these ‘persuasive communication devices’ carefully. In particular, they must be explicit about the limitations of their work, avoid obfuscation, and resist the temptation to oversell their results. Here we discuss a list of persuasive communication devices and we encourage authors, as well as reviewers and editors, to think carefully about their use.
Background: Variants in CLCN4 are implicated in neurodevelopmental disorder, X-linked intellectual disability, and epileptic encephalopathy. CLCN4 encodes ClC-4, which is hypothesized to play a role in ion homeostasis and intracellular trafficking. ClC-4 relies on its formation of heterodimers with ClC-3, which possesses signals for target organelles. Methods: Case-Series. Then, we performed heterologous expression, patch-clamp electrophysiology, confocal microscopy, and protein biochemistry experiments to characterize our patients’ ClC-4 variants. Results: All three male patients had developmental and epileptic encephalopathy. Patients #1 and #2 had normal-appearing brains on MRI and no dysmorphic features. Patient #3 had: microcephaly, microsomia, complete agenesis of the corpus-callosum; and, cerebellar and brainstem hypoplasia. Patient #1 had recurrent status epilepticus separated by months of seizure freedom, while Patient #2 and #3 had brief, daily seizures. The p.Gly342Arg variant impaired the heterodimerization capability of ClC-4. The p.Ile549Leu and p.Asp89Asn variants exhibited early transport-activation, with p.Asp89Asn favouring higher transport-activity of ClC-4. Conclusions: We extend the phenotypic spectrum of CLCN4 variants and demonstrate the pathological functional-consequences of three previously unclassified variants. The p.Gly342Arg variant lead to a loss-of-function phenotype; however, the p.Ile549Leu and p.Asp89Asn variants likely caused gain-of-function phenotypes. Targeted animal or induced pluripotent stem-cell models are needed to further understand epileptogenic mechanisms of CLCN4 variants.
of a long-lived ZBP in gate parameter space, whereas additional data shows that the ZBP is absent in most of the gate parameter space. We find this a more significant problem.
