Variation in early life maternal care predicts later long range frontal cortex synapse development in mice

Empirical and theoretical work suggests that early postnatal experience may inform later developing synaptic connectivity to adapt the brain to its environment. We hypothesized that early maternal experience may program the development of synaptic density on long range frontal cortex projections. To test this idea, we used maternal separation (MS) to generate environmental variability and examined how MS affected 1) maternal care and 2) synapse density on virally-labeled long range axons of offspring reared in MS or control conditions. We found that MS and variation in maternal care predicted bouton density on dorsal frontal cortex axons that terminated in the basolateral amygdala (BLA) and dorsomedial striatum (DMS) with more, fragmented care associated with higher density. The effects of maternal care on these distinct axonal projections of the frontal cortex were manifest at different ages. Maternal care measures were correlated with frontal cortex → BLA bouton density at mid-adolescence postnatal (P) day 35 and frontal cortex → DMS bouton density in adulthood (P85). Meanwhile, we found no evidence that MS or maternal care affected bouton density on ascending orbitofrontal cortex (OFC) or BLA axons that terminated in the dorsal frontal cortices. Our data show that variation in early experience can alter development in a circuit-specific and age-dependent manner that may be relevant to early life adversity.

A. Wren Thomas, Kristen Delevich, Irene Chang, Linda Wilbrecht, Variation in early life maternal care predicts later long range frontal cortex synapse development in mice, Developmental Cognitive Neuroscience (2009)
https://doi.org/10.1016/j.dcn.2019.100737, http://www.sciencedirect.com/science/article/pii/S187892931930324X

Variation in early life maternal care predicts later long range frontal cortex synapse development in mice2019-11-20T23:02:33+00:00

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

Adolescence and “Late Blooming” Synapses of the Prefrontal Cortex

The maturation of the prefrontal cortex (PFC) during adolescence is thought to be important for cognitive and affective development and mental health risk. Whereas many summaries of adolescent development have focused on dendritic spine pruning and gray matter thinning in the PFC during adolescence, we highlight recent rodent data from our laboratory and others to call attention to continued synapse formation and plasticity in the adolescent period in specific cell types and circuits. In particular, we highlight changes in inhibitory neurotransmission onto intratelencephalic (IT-type) projecting cortical neurons and late expansion of connectivity between the amygdala and PFC and the ventral tegmental area and PFC. Continued work on these “late blooming” synapses in specific cell types and circuits, and their interrelationships, will illuminate new opportunities for understanding and shaping the biology of adolescent development. We also address which aspects of adolescent PFC development are dependent on pubertal processes.

Kristen Delevich, A. Wren Thomas, and Linda E. Wilbrecht, Adolescence and “Late Blooming” Synapses of the Prefrontal Cortex [local pdf], Cold Spring Harb Symp Quant Biol (2019)

Adolescence and “Late Blooming” Synapses of the Prefrontal Cortex2019-02-01T12:32:47+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

Long-range orbitofrontal and amygdala axons show divergent patterns of maturation in the frontal cortex across adolescence

The adolescent transition from juvenile to adult is marked by anatomical and functional remodeling of brain networks. Currently, the cellular and synaptic level changes underlying the adolescent transition are only coarsely understood. Here, we use two-photon imaging to make time-lapse observations of long-range axons that innervate the frontal cortex in the living brain. We labeled cells in the orbitofrontal cortex (OFC) and basolateral amygdala (BLA) and imaged their axonal afferents to the dorsomedial prefrontal cortex (dmPFC). We also imaged the apical dendrites of dmPFC pyramidal neurons. Images were taken daily in separate cohorts of juvenile (P24–P28) and young adult mice (P64–P68), ages where we have previously discovered differences in dmPFC dependent decision-making. Dendritic spines were pruned across this peri-adolescent period, while BLA and OFC afferents followed alternate developmental trajectories. OFC boutons showed no decrease in density, but did show a decrease in daily bouton gain and loss with age. BLA axons showed an increase in both bouton density and daily bouton gain at the later age, suggesting a delayed window of enhanced plasticity. Our findings reveal projection specific maturation of synaptic structures within a single frontal region and suggest that stabilization is a more general characteristic of maturation than pruning.

Johnson CM, Loucks A, Peckler H, Thomas AW, Janak P, Wilbrecht L. (in press) Long-range orbitofrontal and amygdala axons show divergent patterns of maturation in the frontal cortex across adolescence. Developmental Cognitive Neuroscience (2016)

Long-range orbitofrontal and amygdala axons show divergent patterns of maturation in the frontal cortex across adolescence2016-02-03T06:01:29+00:00

Early maternal separation impacts cognitive flexibility at the age of first independence in mice

Early life adversity is associated with increased risk for mental and physical health problems, including substance abuse. Changes in neural development caused by early life insults could cause or complicate these conditions. Maternal separation (MS) is a model of early adversity for rodents. Clear effects of MS have been shown on behavioral flexibility in rats, but studies of effects of MS on cognition in mice have been mixed. We hypothesized that previous studies focused on adult mice may have overlooked a developmental transition point when juvenile mice exhibit greater flexibility in reversal learning. Here, using a 4-choice reversal learning task we find that early MS leads to decreased flexibility in post-weaning juvenile mice, but no significant effects in adults. In a further study of voluntary ethanol consumption, we found that adult mice that had experienced MS showed greater cumulative 20% ethanol consumption in an intermittent access paradigm compared to controls. Our data confirm that the MS paradigm can reduce cognitive flexibility in mice and may enhance risk for substance abuse. We discuss possible interpretations of these data as stress-related impairment or adaptive earlier maturation in response to an adverse environment.

A. Wren Thomas, Natalia Caporale, Claudia Wu, Linda Wilbrecht, Early maternal separation impacts cognitive flexibility at the age of first independence in mice, Developmental Cognitive Neuroscience, Available online 19 October 2015, ISSN 1878-9293, http://dx.doi.org/10.1016/j.dcn.2015.09.005.
(http://www.sciencedirect.com/science/article/pii/S187892931530030X)
Keywords: Development; Reversal; Prefrontal; Perseveration; Stress; Neglect

Early maternal separation impacts cognitive flexibility at the age of first independence in mice2015-11-01T15:57:07+00:00

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