Adolescent and adult mice use both incremental reinforcement learning and short term memory when learning concurrent stimulus-action associations

Computational modeling has revealed that human research participants use both rapid working memory (WM) and incremental reinforcement learning (RL) (RL+WM) to solve a simple instrumental learning task, relying on WM when the number of stimuli is small and supplementing with RL when the number of stimuli exceeds WM capacity. Inspired by this work, we examined which learning systems and strategies are used by adolescent and adult mice when they first acquire a conditional associative learning task. In a version of the human RL+WM task translated for rodents, mice were required to associate odor stimuli (from a set of 2 or 4 odors) with a left or right port to receive reward. Using logistic regression and computational models to analyze the first 200 trials per odor, we determined that mice used both incremental RL and stimulus-insensitive, one-back strategies to solve the task. While these one-back strategies may be a simple form of short-term or working memory, they did not approximate the boost to learning performance that has been observed in human participants using WM in a comparable task. Adolescent and adult mice also showed comparable performance, with no change in learning rate or softmax beta parameters with adolescent development and task experience. However, reliance on a one-back perseverative, win-stay strategy increased with development in males in both odor set sizes. Our findings advance a simple conditional associative learning task and new models to enable the isolation and quantification of reinforcement learning alongside other strategies mice use while learning to associate stimuli with rewards within a single behavioral session. These data and methods can inform and aid comparative study of reinforcement learning across species.

Juliana B. Chase, Liyu Xia, Lung-Hao Tai, Wan Chen Lin, Anne G.E. Collins, Linda Wilbrecht, Adolescent and adult mice use both incremental reinforcement learning and short term memory when learning concurrent stimulus-action associations, bioRxiv 2024.04.29.591768; doi: https://doi.org/10.1101/2024.04.29.591768

Adolescent and adult mice use both incremental reinforcement learning and short term memory when learning concurrent stimulus-action associations2024-05-20T09:10:20+00:00

The maturation of exploratory behavior in adolescent Mus spicilegus on two photoperiods

Dispersal from the natal site or familial group is a core milestone of adolescent development in many species. A wild species of mouse, Mus spicilegus, presents an exciting model in which to study adolescent development and dispersal because it shows different life history trajectory depending on season of birth. M. spicilegus born in spring and summer on long days (LD) disperse in the first 3 months of life, while M. spicilegus born on shorter autumnal days (SD) delay dispersal through the wintertime. We were interested in using these mice in a laboratory context to compare age-matched mice with differential motivation to disperse. To first test if we could find a proxy for dispersal related behavior in the laboratory environment, we measured open field and novel object investigation across development in M. spicilegus raised on a LD 12 h:12 h light:dark cycle. We found that between the first and second month of life, distance traveled and time in center of the open field increased significantly with age in M. spicilegus. Robust novel object investigation was observed in all age groups and decreased between the 2nd and 3rd month of life in LD males. Compared to male C57BL/6 mice, male M. spicilegus traveled significantly longer distances in the open field but spent less time in the center of the field. However, when a novel object was placed in the center of the open field, Male M. spicilegus, were significantly more willing to contact and mount it. To test if autumnal photoperiod affects exploratory behavior in M. spicilegus in a laboratory environment, we reared a cohort of M. spicilegus on a SD 10 h:14 h photoperiod and tested their exploratory behavior at P60-70. At this timepoint, we found SD rearing had no effect on open field metrics, but led to reduced novel object investigation. We also observed that in P60-70 males, SD reared M. spicilegus weighed less than LD reared M. spicilegus. These observations establish that SD photoperiod can delay weight gain and blunt some, but not all forms of exploratory behavior in adolescent M. spicilegus.

Noah G. Cryns, Wan Chen Lin, Niloofar Motahari, Oliver J. Krentzman, Weihang Chen, George Prounis, Linda Wilbrecht, The maturation of exploratory behavior in adolescent Mus spicilegus on two photoperiods, Front. Behav. Neurosci., Nov. 4 2022, Sec. Individual and Social Behaviors
https://doi.org/10.3389/fnbeh.2022.988033

The maturation of exploratory behavior in adolescent Mus spicilegus on two photoperiods2022-11-07T12:47:22+00:00

Activation, but not inhibition, of the indirect pathway disrupts choice rejection in a freely moving, multiple-choice foraging task

The dorsomedial striatum (DMS) plays a key role in action selection, but less is known about how direct and indirect pathway spiny projection neurons (dSPNs and iSPNs, respectively) contribute to choice rejection in freely moving animals. Here, we use pathway-specific chemogenetic manipulation during a serial choice foraging task to test the role of dSPNs and iSPNs in learned choice rejection. We find that chemogenetic activation, but not inhibition, of iSPNs disrupts rejection of nonrewarded choices, contrary to predictions of a simple “select/suppress” heuristic. Our findings suggest that iSPNs’ role in stopping and freezing does not extend in a simple fashion to choice rejection in an ethological, freely moving context. These data may provide insights critical for the successful design of interventions for addiction or other conditions in which it is desirable to strengthen choice rejection.

Kristen Delevich,  Benjamin Hoshal, Lexi Z. Zhou, Yuting Zhang, Satya Vedula, Wan Chen Lin, Juliana Chase, Anne G.E. Collins, Linda Wilbrecht, Activation, but not inhibition, of the indirect pathway disrupts choice rejection in a freely moving, multiple-choice foraging task, 40(4) Cell Reports 111129 (July 26, 2022). DOI: https://doi.org/10.1016/j.celrep.2022.111129

Activation, but not inhibition, of the indirect pathway disrupts choice rejection in a freely moving, multiple-choice foraging task2022-07-29T03:19:24+00:00

Transient food insecurity during the juvenile-adolescent period affects adult weight, cognitive flexibility, and dopamine neurobiology

A major challenge for neuroscience, public health, and evolutionary biology is to understand the effects of scarcity and uncertainty on the developing brain. Currently, a significant fraction of children and adolescents worldwide experience insecure access to food. The goal of our work was to test in mice whether the transient experience of insecure versus secure access to food during the juvenile-adolescent period produced lasting differences in learning, decision-making, and the dopamine system in adulthood. We manipulated feeding schedules in mice from postnatal day (P)21 to P40 as food insecure or ad libitum and found that when tested in adulthood (after P60), males with different developmental feeding history showed significant differences in multiple metrics of cognitive flexibility in learning and decision-making. Adult females with different developmental feeding history showed no differences in cognitive flexibility but did show significant differences in adult weight. We next applied reinforcement learning models to these behavioral data. The best fit models suggested that in males, developmental feeding history altered how mice updated their behavior after negative outcomes. This effect was sensitive to task context and reward contingencies. Consistent with these results, in males, we found that the two feeding history groups showed significant differences in the AMPAR/NMDAR ratio of excitatory synapses on nucleus-accumbens-projecting midbrain dopamine neurons and evoked dopamine release in dorsal striatal targets. Together, these data show in a rodent model that transient differences in feeding history in the juvenile-adolescent period can have significant impacts on adult weight, learning, decision-making, and dopamine neurobiology.

Wan Chen Lin, Christine Liu, Polina Kosillo, Lung-Hao Tai, Ezequiel Galarce, Helen S. Bateup, Stephan Lammel, Linda Wilbrecht,
Transient food insecurity during the juvenile-adolescent period affects adult weight, cognitive flexibility, and dopamine neurobiology,
Current Biology, ISSN 0960-9822, (2022) https://doi.org/10.1016/j.cub.2022.06.089 https://www.sciencedirect.com/science/article/pii/S0960982222010946

Transient food insecurity during the juvenile-adolescent period affects adult weight, cognitive flexibility, and dopamine neurobiology2022-07-21T23:12:30+00:00

Making sense of strengths and weaknesses observed in adolescent laboratory rodents

During adolescence, rodents disperse from their natal site, find a new home, and navigate social relationships and threats. Although rats and mice in the laboratory cannot fully express these natural behaviors, they show striking changes in their affective and cognitive behavior across the adolescent period. In some laboratory-based behavior metrics, adolescent rodents fail to show the same behaviors expressed by adults, but in other metrics, adolescent behavioral performance is more robust or more flexible than at other ages. These data are often interpreted in light of proximate level analysis of development of neural circuits. It is also informative to attempt ultimate-level explanations and consider how sex and species-specific adolescent behavioral changes support dispersal, foraging, and social interactions in the wild.

Wan Chen Lin, Linda Wilbrecht, Making sense of strengths and weaknesses observed in adolescent laboratory rodents, Current Opinion in Psychology, Volume 45, 2022, 101297, ISSN 2352-250X, https://doi.org/10.1016/j.copsyc.2021.12.009, https://www.sciencedirect.com/science/article/pii/S2352250X21002499

Making sense of strengths and weaknesses observed in adolescent laboratory rodents2022-06-18T20:42:23+00:00

Dr. Wan Chen Lin

Wan Chen Lin received her Ph.D. in behavioral and systems neuroscience. Congratulations Dr. Lin!

Dr. Wan Chen Lin2021-06-02T16:26:54+00:00

A role for adaptive developmental plasticity in learning and decision making

From both a medical and educational perspective, there is enormous value to understanding the environmental factors that sculpt learning and decision making. These questions are often approached from proximate levels of analysis, but may be further informed by the adaptive developmental plasticity framework used in evolutionary biology. The basic adaptive developmental plasticity framework posits that biological sensitive periods evolved to use information from the environment to sculpt emerging phenotypes. Here, we lay out how we can apply this framework to learning and decision making in the mammalian brain and propose a working model in which dopamine neurons and their activity may serve to inform downstream circuits about environmental statistics. More widespread use of this evolutionary framework and its associated models can help inform and guide basic research and intervention science.

Wan Chen Lin, Kristen Delevich, Linda Wilbrecht, A role for adaptive developmental plasticity in learning and decision making, 36 Current Opinion in Behavioral Sciences pp 48–54 (2020), https://doi.org/10.1016/j.cobeha.2020.07.010, http://www.sciencedirect.com/science/article/pii/S2352154620301121

A role for adaptive developmental plasticity in learning and decision making2021-06-02T16:28:40+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

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

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