Imaging striatal dopamine release using a nongenetically encoded near infrared fluorescent catecholamine nanosensor

Neuromodulation plays a critical role in brain function in both health and disease, and new tools that capture neuromodulation with high spatial and temporal resolution are needed. Here, we introduce a synthetic catecholamine nanosensor with fluorescent emission in the near infrared range (1000–1300 nm), near infrared catecholamine nanosensor (nIRCat). We demonstrate that nIRCats can be used to measure electrically and optogenetically evoked dopamine release in brain tissue, revealing hotspots with a median size of 2 µm. We also demonstrated that nIRCats are compatible with dopamine pharmacology and show D2 autoreceptor modulation of evoked dopamine release, which varied as a function of initial release magnitude at different hotspots. Together, our data demonstrate that nIRCats and other nanosensors of this class can serve as versatile synthetic optical tools to monitor neuromodulatory neurotransmitter release with high spatial resolution.

Abraham G. Beyene, et al., Imaging striatal dopamine release using a nongenetically encoded near infrared fluorescent catecholamine nanosensor, 5(7) Science Advances eaaw3108 (2019)(local PDF).

Imaging striatal dopamine release using a nongenetically encoded near infrared fluorescent catecholamine nanosensor2019-07-17T19:51:56+00:00

Mice engineered to mimic a common Val66Met polymorphism in the BDNF gene show greater sensitivity to reversal in environmental contingencies

A common human polymorphism in the gene that encodes brain derived neurotrophic factor (BDNF), Val66Met, is considered a marker of vulnerability for mental health issues and has been associated with cognitive impairment. An alternate framework has been proposed in which “risk alleles” are reinterpreted as “plasticity alleles” that confer vulnerability in adverse environments and positive effects in neutral or positive environments (Belsky et al., 2009). These frameworks produce divergent predictions for tests of learning and cognitive flexibility. Here, we examined multiple aspects of learning and cognitive flexibility in a relatively new BDNF Val66Met mouse model (BDNF Val68Met, Warnault et al., 2016), including multiple choice discrimination and reversal, go/no-go learning and reversal, and appetitive extinction learning. We found that mice homozygous for the Met allele show more efficient reversal learning in two different paradigms, but learn at rates comparable to Val homozygotes on the multiple choice discrimination task, a go/no-go task, and in appetitive extinction. Our results dissociate reversal performance from go/no-go learning and appetitive extinction and support the plasticity allele framework that suggests BDNF Met carriers are potentially more sensitive to changes in the environment.

Angela Vandenberg, Wan Chen Lin, Lung-Hao Tai, Dorit Ron, Linda Wilbrecht, Mice engineered to mimic a common Val66Met polymorphism in the BDNF gene show greater sensitivity to reversal in environmental contingencies, 34 Developmental Cognitive Neuroscience 34–41 (2018)

Mice engineered to mimic a common Val66Met polymorphism in the BDNF gene show greater sensitivity to reversal in environmental contingencies2019-02-02T21:38:12+00:00

Imaging Striatal Dopamine Release Using a Non-Genetically Encoded Near-Infrared Fluorescent Catecholamine Nanosensor

Neuromodulation plays a critical role in brain function in both health and disease. New optical tools, and their validation in biological tissues, are needed that can image neuromodulation with high spatial and temporal resolution, which will add an important new dimension of information to neuroscience research. Here, we demonstrate the use of a catecholamine nanosensor with fluorescent emission in the 1000-1300 nm near-infrared window to measure dopamine transmission in ex vivo brain slices. These near-infrared catecholamine nanosensors (nIRCats) represent a broader class of nanosensors that can be synthesized from non-covalent conjugation of single wall carbon nanotubes (SWNT) with single strand oligonucleotides. We show that nIRCats can be used to detect catecholamine efflux in brain tissue driven by both electrical stimulation or optogenetic stimulation. Spatial analysis of electrically-evoked signals revealed dynamic regions of interest approximately 2 microns in size in which transients scaled with simulation intensity. Optogenetic stimulation of dopaminergic terminals produced similar transients, whereas optogenetic stimulation of glutamatergic terminals showed no effect on nIRCat signal. Bath application of nomifensine prolonged nIRCat fluorescence signal, consistent with reuptake blockade of dopamine. We further show that the chemically synthetic molecular recognition elements of nIRCats permit measurement of dopamine dynamics in the presence of dopamine receptor agonists and antagonists. These nIRCat nanosensors may be advantageous for future use because i) they do not require virus delivery, gene delivery, or protein expression, ii) their near-infrared fluorescence facilitates imaging in optically scattering brain tissue and is compatible for use in conjunction with other optical neuroscience tool sets, iii) the broad availability of unique near-infrared colors have the potential for simultaneous detection of multiple neurochemical signals, and iv) they are compatible with pharmacology. Together, these data suggest nIRCats and other nanosensors of this class can serve as versatile new optical tools to report dynamics of extracellular neuromodulation in the brain.

Abraham G Beyene, Kristen Delevich, Jackson Travis Del Bonis ODonnell, David J Piekarski, Wan Chen Lin, A Wren Thomas, Sarah J Yang, Polina Kosillo, Darwin Yang, Linda Wilbrecht, Markita P Landry, Imaging Striatal Dopamine Release Using a Non-Genetically Encoded Near-Infrared Fluorescent Catecholamine Nanosensor, biorxiv preprint (2018)

Imaging Striatal Dopamine Release Using a Non-Genetically Encoded Near-Infrared Fluorescent Catecholamine Nanosensor2019-02-02T22:06:38+00:00

Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex?

Postnatal brain development is studded with sensitive periods during which experience dependent plasticity is enhanced. This enables rapid learning from environmental inputs and reorganization of cortical circuits that matches behavior with environmental contingencies. Significant headway has been achieved in characterizing and understanding sensitive period biology in primary sensory cortices, but relatively little is known about sensitive period biology in associative neocortex. One possible mediator is the onset of puberty, which marks the transition to adolescence, when animals shift their behavior toward gaining independence and exploring their social world. Puberty onset correlates with reduced behavioral plasticity in some domains and enhanced plasticity in others, and therefore may drive the transition from juvenile to adolescent brain function. Pubertal onset is also occurring earlier in developed nations, particularly in unserved populations, and earlier puberty is associated with vulnerability for substance use, depression and anxiety. In the present article we review the evidence that supports a causal role for puberty in developmental changes in the function and neurobiology of the associative neocortex. We also propose a model for how pubertal hormones may regulate sensitive period plasticity in associative neocortex. We conclude that the evidence suggests puberty onset may play a causal role in some aspects of associative neocortical development, but that further research that manipulates puberty and measures gonadal hormones is required. We argue that further work of this kind is urgently needed to determine how earlier puberty may negatively impact human health and learning potential.

David J. Piekarski, Carolyn Johnson, Josiah R. Boivin, A. Wren Thomas, Wan Chen Lin, Kristen Delevich, Ezequiel Galarce and Linda Wilbrecht, Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex?, Brain Research, http://dx.doi.org/10.1016/j.brainres.2016.08.042

Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex?2016-09-03T06:57:13+00:00

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