Pubmed: Wilbrecht L
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
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)
Rules encompass cue-action-outcome associations used to guide decisions and strategies in a specific context. Subregions of the frontal cortex including the orbitofrontal cortex (OFC) and dorsomedial prefrontal cortex (dmPFC) are implicated in rule learning, although changes in structural connectivity underlying rule learning are poorly understood. We imaged OFC axonal projections to dmPFC during training in a multiple choice foraging task and used a reinforcement learning model to quantify explore–exploit strategy use and prediction error magnitude. Here we show that rule training, but not experience of reward alone, enhances OFC bouton plasticity. Baseline bouton density and gains during training correlate with rule exploitation, while bouton loss correlates with exploration and scales with the magnitude of experienced prediction errors. We conclude that rule learning sculpts frontal cortex interconnectivity and adjusts a thermostat for the explore–exploit balance.
Johnson C, Peckler H,Tai LH, Wilbrecht L., Rule learning enhances structural plasticity of long range axons in frontal cortex. Nature Communications (2016)
The basal ganglia (BG) are critical for adaptive motor control, but the circuit principles underlying their pathway-specific modulation of target regions are not well understood. Here, we dissect the mechanisms underlying BG direct and indirect pathway-mediated control of the mesencephalic locomotor region (MLR), a brainstem target of BG that is critical for locomotion. We optogenetically dissect the locomotor function of the three neurochemically distinct cell types within the MLR: glutamatergic, GABAergic, and cholinergic neurons. We find that the glutamatergic subpopulation encodes locomotor state and speed, is necessary and sufficient for locomotion, and is selectively innervated by BG. We further show activation and suppression, respectively, of MLR glutamatergic neurons by direct and indirect pathways, which is required for bidirectional control of locomotion by BG circuits. These findings provide a fundamental understanding of how BG can initiate or suppress a motor program through cell-type-specific regulation of neurons linked to specific actions.
Thomas K. Roseberry, A. Moses Lee, Arnaud L. Lalive, Linda Wilbrecht, Antonello Bonci, Anatol C. Kreitzer, Cell-Type-Specific Control of Brainstem Locomotor Circuits by Basal Ganglia, 64(3) Cell (Jan. 2016), http://www.cell.com/cell/abstract/S0092-8674%2815%2901701-8
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.
Keywords: Development; Reversal; Prefrontal; Perseveration; Stress; Neglect
The BDNF Val68 to Met Polymorphism Increases Compulsive Alcohol Drinking In Mice Which Is Reversed By TrkB Activation
The Val66 to Met polymorphism within the brain-derived neurotrophic factor (BDNF) sequence reduces activity-dependent BDNF release, and is associated with psychiatric disorders in humans. Alcoholism is one of the most prevalent psychiatric diseases. Here, we tested the hypothesis that this polymorphism increases the severity of alcohol abuse disorders.
We generated transgenic mice carrying the mouse homolog of the human Met66BDNF allele (Met68BDNF), and used alcohol-drinking paradigms in combination with viral-mediated gene delivery and pharmacology.
We found that Met68BDNF mice consumed excessive amounts of alcohol and continued to drink despite negative consequences, a hallmark of addiction. Importantly, compulsive alcohol intake was reversed by overexpression of the wild-type Val68BDNF allele in the ventromedial prefrontal cortex of the Met68BDNF mice, or by systemic administration of the TrkB agonist, LM22A-4.
Our findings suggest that carrying the Met66BDNF allele increases the risk of developing uncontrolled and excessive alcohol drinking that can be reversed by directly activating the BDNF receptor, TrkB. Importantly, this work identifies a potential therapeutic strategy for the treatment of compulsive alcohol drinking in humans carrying the Met66BDNF allele.
Vincent Warnault, Emmanuel Darcq, Nadege Morisot, Khanhky Phamluong, Linda Wilbrecht, Stephen M. Massa, Frank M. Longo, and Dorit Ron, The BDNF Val68 to Met Polymorphism Increases Compulsive Alcohol Drinking In Mice Which Is Reversed By TrkB Activation. Biological Psychiatry
Brief cognitive training interventions in young adulthood promote long-term resilience to drug-seeking behavior
Environmental stress and deprivation increase vulnerability to substance use disorders in humans and promote drug-seeking behavior in animal models. In contrast, experiences of mastery and stability may shape neural circuitry in ways that build resilience to future challenges. Cognitive training offers a potential intervention for reducing vulnerability in the face of environmental stress or deprivation. Here, we test the hypothesis that brief cognitive training can promote long-term resilience to one measure of drug-seeking behavior, cocaine conditioned place preference (CPP), in mice. In young adulthood, mice underwent cognitive training, received rewards while exploring a training arena (i.e. yoked control), or remained in their home cages. Beginning 4 weeks after cessation of training, we conditioned mice in a CPP paradigm and then tested them weekly for CPP maintenance or daily for CPP extinction. We found that a brief 9-day cognitive training protocol reduced maintenance of cocaine CPP when compared to standard housed and yoked conditions. This beneficial effect persisted long after cessation of the training, as mice remained in their home cages for 4 weeks between training and cocaine exposure. When mice were tested for CPP on a daily extinction schedule, we found that all trained and yoked groups that left their home cages to receive rewards in a training arena showed significant extinction of CPP, while mice kept in standard housing for the same period did not extinguish CPP. These data suggest that in early adulthood, deprivation may confer vulnerability to drug-seeking behavior and that brief interventions may promote long-term resilience.
Josiah Boivin, Denise Piscopo, Linda Wilbrecht, Brief cognitive training interventions in young adulthood promote long-term resilience to drug-seeking behavior. Neuropharmacology
Adolescent maturation of inhibitory inputs onto cingulate cortex neurons is cell-type specific and TrkB dependent
The maturation of inhibitory circuits during adolescence may be tied to the onset of mental health disorders such as schizophrenia. Neurotrophin signaling likely plays a critical role in supporting inhibitory circuit development and is also implicated in psychiatric disease. Within the neocortex, subcircuits may mature at different times and show differential sensitivity to neurotrophin signaling. We measured miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSCs) in Layer 5 cell-types in the mouse anterior cingulate (Cg) across the periadolescent period. We differentiated cell-types mainly by Thy1 YFP transgene expression and also retrobead injection labeling in the contralateral Cg and ipsilateral pons. We found that YFP− neurons and commissural projecting neurons had lower frequency of mIPSCs than neighboring YFP+ neurons or pons projecting neurons in juvenile mice (P21–25). YFP− neurons and to a lesser extent commissural projecting neurons also showed a significant increase in mIPSC amplitude during the periadolescent period (P21–25 vs. P40–50), which was not seen in YFP+ neurons or pons projecting neurons. Systemic disruption of tyrosine kinase receptor B (TrkB) signaling during P23–50 in TrkBF616A mice blocked developmental changes in mIPSC amplitude, without affecting miniature excitatory post synaptic currents (mEPSCs). Our data suggest that the maturation of inhibitory inputs onto Layer 5 pyramidal neurons is cell-type specific. These data may inform our understanding of adolescent brain development across species and aid in identifying candidate subcircuits that may show greater vulnerability in mental illness.
Vandenberg A, Piekarski DJ, Caporale N, Munoz-Cuevas FJ and Wilbrecht L (2015) Adolescent maturation of inhibitory inputs onto cingulate cortex neurons is cell-type specific and TrkB dependent. Front. Neural Circuits 9:5. doi: 10.3389/fncir.2015.00005
Review: Between the Primate and “Reptilian” Brain: Rodent Models Demonstrate the Role of the Corticostriatal Circuits in Decision Making
Decision making can be defined as the flexible integration and transformation of information from the external world into action. Recently, the development of novel genetic tools and new behavioral paradigms has made it attractive to study behavior of all kinds in rodents. By some perspectives, rodents are not an acceptable model for the study of decision making due to their simpler behavior often attributed to their less extensive cortical development when compared to non-human primates. We argue that decision making can be approached with a common framework across species. We review insights from comparative anatomy that suggest the expansion of cortical-striatal connectivity is a key development in evolutionary increases in behavioral flexibility. We briefly review studies that establish a role for corticostriatal circuits in integrative decision making. Finally, we provide an overview of a few recent, highly complementary rodent decision making studies using genetic tools, revealing with new cellular and tempo- ral resolution how, when and where information can be integrated and compared in striatal circuits to influence choice.
Lee AM et al. Between the primate and ‘reptilian’ brain: Rodent models demonstrate the role of corticostriatal circuits in decision making. Neuroscience (2015), http://dx.doi.org/10.1016/j.neuroscience.2014.12.042
Sensory processing is dependent upon behavioral state. In mice, locomotion is accompanied by changes in cortical state and enhanced visual re- sponses. Although recent studies have begun to elucidate intrinsic cortical mechanisms underlying this effect, the neural circuits that initially couple locomotion to cortical processing are unknown. The mesencephalic locomotor region (MLR) has been shown to be capable of initiating running and is associated with the ascending reticular activating system. Here, we find that optogenetic stimulation of the MLR in awake, head-fixed mice can induce both locomotion and increases in the gain of cortical responses. MLR stimulation below the threshold for overt movement similarly changed cortical pro- cessing, revealing that MLR’s effects on cortex are dissociable from locomotion. Likewise, stimulation of MLR projections to the basal forebrain also enhanced cortical responses, suggesting a pathway linking the MLR to cortex. These studies demon- strate that the MLR regulates cortical state in parallel with locomotion.
A. Moses Lee, Jennifer L. Hoy, Antonello Bonci, Linda Wilbrecht, Michael P. Stryker, and Cristopher M. Niell, Identification of a Brainstem Circuit Regulating Visual Cortical State in Parallel with Locomotion, Neuron 83, 455–466, July 16, 2014, http://dx.doi.org/10.1016/j.neuron.2014.06.031
Cocaine-induced structural plasticity in frontal cortex correlates with conditioned place preference
Contextual cues associated with previous drug exposure can trigger drug craving and seeking, and form a substantial obstacle in substance use recovery. Using in vivo imaging in mice, we found that cocaine administration induced a rapid increase in the formation and accumulation of new dendritic spines, and that measures of new persistent spine gain correlated with cocaine conditioned place preference. Our data suggest that new persistent spine formation in the frontal cortex may be involved in stimulant-related learning driving appetitive behavior.
Francisco Javier Muñoz-Cuevas, Jegath Athilingam, Denise Piscopo, Linda Wilbrecht, Cocaine-induced structural plasticity in frontal cortex correlates with conditioned place preference, Nature Neuroscience (2013) doi:10.1038/nn.3498 (Full Text)
In changing environments, animals must adaptively select actions to achieve their goals. In tasks involving goal-directed action selection, striatal neural activity has been shown to represent the value of competing actions. Striatal representations of action value could potentially bias responses toward actions of higher value. However, no study to date has demonstrated the direct effect of distinct striatal pathways in goal-directed action selection. We found that transient optogenetic stimulation of dorsal striatal dopamine D1 and D2 receptor–expressing neurons during decision-making in mice introduced opposing biases in the distribution of choices. The effect of stimulation on choice was dependent on recent reward history and mimicked an additive change in the action value. Although stimulation before and during movement initiation produced a robust bias in choice behavior, this bias was substantially diminished when stimulation was delayed after response initiation. Together, our data suggest that striatal activity is involved in goal-directed action selection.
Lung-Hao Tai*, A Moses Lee*, Nora Benavidez, Antonello Bonci, Linda Wilbrecht, Transient stimulation of distinct subpopulations of striatal neurons mimics changes in action value Nature Neuroscience 15, 1281–1289, (2012) doi:10.1038/nn.3188 (Full Text)
We hypothesized that decision-making strategies in juvenile animals, rather than being immature, are optimized to navigate the uncertainty and instability likely to be encountered in the environment at the time of the animal’s transition to independence. We tested juvenile and young adult mice on discrimination and reversal of a 4-choice and 2-choice odor-based foraging task. Juvenile mice (P26–27) learned a 4-choice discrimination and reversal faster than adults (P60–70), making fewer perseverative and distraction errors. Juvenile mice had shorter choice latencies and more focused search strategies. In both ages, performance of the task was significantly impaired by a lesion of the dorsomedial frontal cortex. Our data show that the frontal cortex can support highly flexible behavior in juvenile mice at a time coincident with weaning and first independence. The unexpected developmental decline in flexibility of behavior one month later suggests that frontal cortex based executive function may not inevitably become more flexible with age, but rather may be developmentally tuned to optimize exploratory and exploitative behavior for each life stage.
Johnson C and Wilbrecht L. 2011. Juvenile mice show greater flexibility in multiple choice reversal learning than adults. Dev Cogn Neurosci. 2011 Oct;1(4):540-51. doi: 10.1016/j.dcn.2011.05.008 (Full Text)
The stabilization of new spines in the barrel cortex is enhanced after whisker trimming, but its relationship to experience-dependent plasticity is unclear. Here we show that in wild-type mice, whisker potentiation and spine stabilization are most pronounced for layer 5 neurons at the border between spared and deprived barrel columns. In homozygote αCaMKII-T286A mice, which lack experience-dependent potentiation of responses to spared whiskers, there is no increase in new spine stabilization at the border between barrel columns after whisker trimming. Our data provide a causal link between new spine synapses and plasticity of adult cortical circuits and suggest that αCaMKII autophosphorylation plays a role in the stabilization but not formation of new spines.
Wilbrecht L, Holtmaat A, Wright N, Fox K, Svoboda K. 2010. Structural plasticity supports experience-dependent functional plasticity of cortical circuits. The Journal of Neuroscience, 7 April 2010, 30(14): 4927-4932; doi: 10.1523/JNEUROSCI.6403-09.2010 (Full Text)
There has been an emerging focus in neuroscience research on circuit-level interaction between multiple brain regions and behavior. This broad circuit-level approach creates a unique opportunity for convergence and collaboration between studies of humans and animal models of cognition.
Wilbrecht L, Shohamy D. 2010. Neural circuits can bridge systems and cognitive neuroscience. Front Hum Neurosci. 3:81 doi: 10.3389/neuro.09.081.2009 (Full Text)