Faculty Bibliography

Azobenzenes are versatile photoswitches that have found widespread use in a variety of fields, ranging from photopharmacology to the material sciences. In addition to regular azobenzenes, the cyclic diazocines have recently emerged. Although diazocines have fascinating conformational and photophysical properties, their use has been limited by their synthetic accessibility. Herein, we present a general, high-yielding protocol that relies on the oxidative cyclization of dianilines. In combination with a modular substrate synthesis, it allows for rapid access to diversely functionalized diazocines on gram scales. Our work systematically explores substituent effects on the photoisomerization and thermal relaxation of diazocines. It will enable their incorporation into a wide variety of functional molecules, unlocking the full potential of these emerging photoswitches. The method can be applied to the synthesis of a new cyclic azobenzene with a nine-membered central ring and distinct properties.

Dystonia is a disabling neurological syndrome characterized by abnormal movements and postures that result from intermittent or sustained involuntary muscle contractions; mutations of DYT1/TOR1A are the most common cause of childhood-onset, generalized, inherited dystonia. Patient and mouse model data strongly support dysregulation of the nigrostriatal dopamine neurotransmission circuit in the presence of the DYT1-causing mutation. To determine striatal medium spiny neuron (MSN) cell-autonomous and non-cell autonomous effects relevant to dopamine transmission, we created a transgenic mouse in which expression of mutant torsinA in forebrain is restricted to MSNs. We assayed electrically evoked and cocaine-enhanced dopamine release and locomotor activity, dopamine uptake, gene expression of dopamine-associated neuropeptides and receptors, and response to the muscarinic cholinergic antagonist, trihexyphenidyl. We found that over-expression of mutant torsinA in MSNs produces complex cell-autonomous and non-cell autonomous alterations in nigrostriatal dopaminergic and intrastriatal cholinergic function, similar to that found in pan-cellular DYT1 mouse models. These data introduce targets for future studies to identify which are causative and which are compensatory in DYT1 dystonia, and thereby aid in defining appropriate therapies.

The methods for electrophysiology in neuroscience have evolved tremendously over the recent years with a growing emphasis on dense-array signal recordings. Such increased complexity and augmented wealth in the volume of data recorded, have not been accompanied by efforts to streamline and facilitate access to processing methods, which too are susceptible to grow in sophistication. Moreover, unsuccessful attempts to reproduce peer-reviewed publications indicate a problem of transparency in science. This growing problem could be tackled by unrestricted access to methods that promote research transparency and data sharing, ensuring the reproducibility of published results. Here, we provide a free, extensive, open-source software that provides data-analysis, data-management and multi-modality integration solutions for invasive neurophysiology. Users can perform their entire analysis through a user-friendly environment without the need of programming skills, in a tractable (logged) way. This work contributes to open-science, analysis standardization, transparency and reproducibility in invasive neurophysiology.

Rumination is strongly and consistently correlated with depression. Although multiple studies have explored the neural correlates of rumination, findings have been inconsistent and the mechanisms underlying rumination remain elusive. Functional brain imaging studies have identified areas in the default mode network (DMN) that appear to be critically involved in ruminative processes. However, a meta-analysis to synthesize the findings of brain regions underlying rumination is currently lacking. Here, we conducted a meta-analysis consisting of experimental tasks that investigate rumination by using Signed Differential Mapping of 14 fMRI studies comprising 286 healthy participants. Furthermore, rather than treat the DMN as a unitary network, we examined the contribution of three DMN subsystems to rumination. Results confirm the suspected association between rumination and DMN activation, specifically implicating the DMN core regions and the dorsal medial prefrontal cortex subsystem. Based on these findings, we suggest a hypothesis of how DMN regions support rumination and present the implications of this model for treating major depressive disorder characterized by rumination.

Rhesus macaques (Macaca mulatta) appear to be robustly risk-seeking in computerized gambling tasks typically used for electrophysiology. This behavior distinguishes them from many other animals, which are risk-averse, albeit measured in more naturalistic contexts. We wondered whether macaques' risk preferences reflect their evolutionary history or derive from the less naturalistic elements of task design associated with the demands of physiological recording. We assessed macaques' risk attitudes in a task that is somewhat more naturalistic than many that have previously been used: subjects foraged at four feeding stations in a large enclosure. Patches (i.e., stations), provided either stochastically or non-stochastically depleting rewards. Subjects' patch residence times were longer at safe than at risky stations, indicating a preference for safe options. This preference was not attributable to a win-stay-lose-shift heuristic and reversed as the environmental richness increased. These findings highlight the lability of risk attitudes in macaques and support the hypothesis that the ecological validity of a task can influence the expression of risk preference.

Photopharmacology relies on ligands that change their pharmacodynamics upon photoisomerization. Many of these ligands are azobenzenes that are thermodynamically more stable in their elongated trans-configuration. Often, they are biologically active in this form and lose activity upon irradiation and photoisomerization to their cis-isomer. Recently, cyclic azobenzenes, so-called diazocines, have emerged, which are thermodynamically more stable in their bent cis-form. Incorporation of these switches into a variety of photopharmaceuticals could convert dark-active ligands into dark-inactive ligands, which is preferred in most biological applications. This "pharmacological sign-inversion" is demonstrated for a photochromic blocker of voltage-gated potassium channels, termed CAL, and a photochromic opener of G protein-coupled inwardly rectifying potassium (GIRK) channels, termed CLOGO.

Sensory systems use stochastic fate specification to increase their repertoire of neuronal types. How these stochastic decisions are coordinated with the development of their targets is unknown. In the Drosophila retina, two subtypes of UV-sensitive R7-photoreceptors are stochastically specified. In contrast, their targets in the brain are specified through a deterministic program. Here, we identify subtypes of the main target of R7, the Dm8 neurons, each specific to the different subtypes of R7s. Dm8 subtypes are produced in excess by distinct neuronal progenitors, independently from R7. Following matching with their cognate R7, supernumerary Dm8s are eliminated by apoptosis. Two interacting cell adhesion molecules, Dpr11 and DIPγ, are essential for the matching of one of the synaptic pairs. These mechanisms allow the qualitative and quantitative matching of R7/Dm8 and permit the stochastic choice made in R7 to propagate to the brain.

Transient periods of childhood hearing loss can induce deficits in aural communication that persist long after auditory thresholds have returned to normal, reflecting long-lasting impairments to the auditory central nervous system. Here, we asked whether these behavioral deficits could be reversed by treating one of the central impairments: reduction of inhibitory strength. Male and female gerbils received bilateral earplugs to induce a mild, reversible hearing loss during the critical period of auditory cortex development. After earplug removal and the return of normal auditory thresholds, we trained and tested animals on an amplitude modulation detection task. Transient developmental hearing loss induced both learning and perceptual deficits, which were entirely corrected by treatment with a selective GABA reuptake inhibitor (SGRI). To explore the mechanistic basis for these behavioral findings, we recorded the amplitudes of GABA_A and GABA_B receptor-mediated inhibitory postsynaptic potentials (IPSPs) in auditory cortical and thalamic brain slices. In hearing loss-reared animals, cortical IPSP amplitudes were significantly reduced within a few days of hearing loss onset, and this reduction persisted into adulthood. SGRI treatment during the critical period prevented the hearing loss-induced reduction of IPSP amplitudes, but when administered after the critical period it only restored GABA_B receptor-mediated IPSP amplitudes. These effects were driven, in part, by the ability of SGRI to upregulate α1 subunit-dependent GABA_A responses. Similarly, SGRI prevented the hearing loss-induced reduction of GABA_A and GABA_B IPSPs in the ventral nucleus of the medial geniculate body. Thus, by maintaining, or subsequently rescuing, GABAergic transmission in the central auditory thalamocortical pathway, some perceptual and cognitive deficits induced by developmental hearing loss can be prevented.SIGNIFICANCE STATEMENTEven a temporary period of childhood hearing loss can induce communication deficits that persist long after auditory thresholds return to normal. These deficits may arise from long-lasting central impairments, including the loss of synaptic inhibition. Here, we asked whether hearing loss-induced behavioral deficits could be reversed by reinstating normal inhibitory strength. Gerbils reared with transient hearing loss displayed both learning and perceptual deficits. However, when animals were treated with a selective GABA reuptake inhibitor during or after hearing loss, behavioral deficits were entirely corrected. This behavioral recovery was correlated with the return of normal thalamic and cortical inhibitory function. Thus, some perceptual and cognitive deficits induced by developmental hearing loss were prevented with a treatment that rescues a central synaptic property.

The inverse Funk transform of high angular resolution diffusion imaging (HARDI) data provides an estimate for the fiber orientation density function (fODF) in white matter (WM). Since the inverse Funk transform is a straightforward linear transformation, this technique, referred to as fiber ball imaging (FBI), offers a practical means of calculating the fODF that avoids the need for a response function or nonlinear numerical fitting. Nevertheless, the accuracy of FBI depends on both the choice of b-value and the number of diffusion-encoding directions used to acquire the HARDI data. To inform the design of optimal scan protocols for its implementation, FBI predictions are investigated here with in vivo data from healthy adult volunteers acquired at 3 T for b-values spanning 1000 to 10,000 s/mm², for diffusion-encoding directions varying in number from 30 to 256 and for TE ranging from 90 to 120 ms. Our results suggest b-values above 4000 s/mm² with at least 64 diffusion-encoding directions are adequate to achieve reasonable accuracy with FBI for calculating axon-specific diffusion measures and for performing WM fiber tractography (WMFT).