Extinguishing the previously acquired fear is critical for the adaptation of an organism to the ever-changing environment, a process requiring the engagement of GABAA receptors (GABAARs). GABAARs consist of tens of structurally, pharmacologically, and functionally heterogeneous subtypes. However, the specific roles of these subtypes in fear extinction remain largely unexplored. Here, we observed that in the medial prefrontal cortex (mPFC), a core region for mood regulation, the extrasynaptically situated, δ-subunit-containing GABAARs [GABAA(δ)Rs], had a permissive role in tuning fear extinction in male mice, an effect sharply contrasting to the established but suppressive role by the whole GABAAR family. First, the fear extinction in individual mice was positively correlated with the level of GABAA(δ)R expression and function in their mPFC. Second, knockdown of GABAA(δ)R in mPFC, specifically in its infralimbic (IL) subregion, sufficed to impair the fear extinction in mice. Third, GABAA(δ)R-deficient mice ...

In patch foraging tasks, animals must decide whether to remain with a depleting resource or to leave it in search of a potentially better source of reward. In such tasks, animals consistently follow the general predictions of optimal foraging theory (the marginal value theorem; MVT): to leave a patch when the reward rate in the current patch depletes to the average reward rate across patches. Prior studies implicate an important role for the anterior cingulate cortex (ACC) in foraging decisions based on MVT: within single trials, ACC activity increases immediately preceding foraging decisions, and across trials, these dynamics are modulated as the value of staying in the patch depletes to the average reward rate. Here, we test whether these activity patterns reflect dynamic encoding of decision-variables and whether these signals are directly involved in decision-making. We developed a leaky accumulator model based on the MVT that generates estimates of decision variables within and across trials, and test...

Alzheimer's disease (AD) is histopathologically characterized by Aβ plaques and the accumulation of hyperphosphorylated Tau species, the latter also constituting key hallmarks of primary tauopathies. Whereas Aβ is produced by amyloidogenic APP processing, APP processing along the competing nonamyloidogenic pathway results in the secretion of neurotrophic and synaptotrophic APPsα. Recently, we demonstrated that APPsα has therapeutic effects in transgenic AD model mice and rescues Aβ-dependent impairments. Here, we examined the potential of APPsα to mitigate Tau-induced synaptic deficits in P301S mice (both sexes), a widely used mouse model of tauopathy. Analysis of synaptic plasticity revealed an aberrantly increased LTP in P301S mice that could be normalized by acute application of nanomolar amounts of APPsα to hippocampal slices, indicating a homeostatic function of APPsα on a rapid time scale. Further, AAV-mediated in vivo expression of APPsα restored normal spine density of CA1 neurons even at stages of...

The sunk cost effect refers to the fact that human decisions are consistently influenced by previous irrecoverable and irrelevant costs. Recent neuroimaging experiments suggest that the dorsolateral prefrontal cortex (dlPFC) plays a pivotal role in the sunk cost effect yet the causal and neurocomputational role of the dlPFC remains elusive. In this study, two cohorts of healthy human male and female adults were recruited to complete a novel two-step decision-making task during the anodal-sham or cathodal-sham high-definition transcranial direct current stimulation (HD-tDCS) over the dlPFC, respectively. Consistent with previous studies, we showed that the sunk cost deterred participants from making further investment and therefore engendered a de-escalation effect. Such behavior can be captured by a weighted mental accounting model with a recalibrated reference point in which the direction and magnitude of the sunk cost effects hinge on the decision weights apportioned to the option values. Interestingly, ...

Aggressive behavior is one of the most conserved social interactions in nature and serves as a crucial evolutionary trait. Serotonin (5-HT) plays a key role in the regulation of our emotions such as anxiety and aggression, but which molecules and mechanisms in the serotonergic system are involved in violent behavior is still unknown. In this study we show that deletion of the P/Q-type calcium channel selectively from serotonergic neurons in the dorsal raphe nuclei (DRN) augments aggressive behavior in male mice, while anxiety is not affected. These mice demonstrated increased induction of the immediate early gene c-fos and in vivo serotonergic firing activity in the DRN. The ventrolateral part of the ventromedial hypothalamus (VHMvl) is also a prominent region of the brain mediating aggression. We confirmed a monosynaptic projection from the DRN to the VHMvl and silencing these projections with an inhibitory designer receptor exclusively activated by a designer drug (DREADD) effectively reduced aggressive ...

Individual differences among human brains exist at many scales, spanning gene expression, white matter tissue properties, and the size and shape of cortical areas. One notable example is an approximately 3-fold range in the size of human primary visual cortex (V1), a much larger range than is found in overall brain size. A previous study (Andrews et al., 1997) reported a correlation between optic tract cross-section area and V1 size in post-mortem human brains, suggesting that there may be a common developmental mechanism for multiple components of the visual pathways. We evaluated the relationship between properties of the optic tract and V1 in a much larger sample of living human brains by analyzing the Human Connectome Project 7 Tesla Retinotopy Dataset (including 107 females and 71 males). This dataset includes retinotopic maps measured with functional MRI (fMRI) and fiber tract data measured with diffusion MRI (dMRI). We found a negative correlation between optic tract fractional anisotropy and V1 sur...

Olfactory information is relayed and processed in the olfactory bulb (OB). Mitral cells (MCs), the principal output excitatory neurons of the OB, are controlled by multiple types of interneurons. However, mechanisms that regulate the activity of OB interneurons are not well understood. We provide evidence that the transmembrane tyrosine kinase ErbB4 is selectively expressed in subsets of OB inhibitory neurons in both male and female mice. ErbB4-positive (ErbB4+) neurons are mainly located in the glomerular layer (GL) and granule cell layer (GCL) and do not express previously defined markers. Optogenetic activation of GL-ErbB4+ neurons promotes theta oscillation, whereas activation of those in the GCL generates gamma oscillations. Stimulation of OB slices with NRG1, a ligand that activates ErbB4, increases GABA transmission onto MCs, suggesting a role of OB NRG1-ErbB4 signaling in olfaction. In accord, ErbB4 mutant mice or acute inhibition of ErbB4 by a chemical genetic approach diminishes GABA transmission...

Active forgetting occurs in many species, but how behavioral control mechanisms influence which memories are forgotten remains unknown. We previously found that when rats need to retrieve a memory to guide exploration, it reduces later retention of other competing memories encoded in that environment. As with humans, this retrieval-induced forgetting relies on prefrontal control processes. Dopaminergic input to the prefrontal cortex is important for executive functions and cognitive flexibility. We found that, in a similar way, retrieval-induced forgetting of competing memories in male rats requires prefrontal dopamine signaling through D1 receptors. Blockade of medial prefrontal cortex D1 receptors as animals encountered a familiar object impaired active forgetting of competing object memories as measured on a later long-term memory test. Inactivation of the ventral tegmental area produced the same pattern of behavior, a pattern that could be reversed by concomitant activation of prefrontal D1 receptors. ...

Active forgetting occurs in many species, but how behavioral control mechanisms influence which memories are forgotten remains unknown. We previously found that when rats need to retrieve a memory to guide exploration, it reduces later retention of other competing memories encoded in that environment. As with humans, this retrieval-induced forgetting relies on prefrontal control processes. Dopaminergic input to the prefrontal cortex is important for executive functions and cognitive flexibility. We found that, in a similar way, retrieval-induced forgetting of competing memories in male rats requires prefrontal dopamine signaling through D1 receptors. Blockade of medial prefrontal cortex D1 receptors as animals encountered a familiar object impaired active forgetting of competing object memories as measured on a later long-term memory test. Inactivation of the ventral tegmental area produced the same pattern of behavior, a pattern that could be reversed by concomitant activation of prefrontal D1 receptors. ...

CRISPR/Cas9-mediated knock-in methods enable the labeling of individual endogenous proteins to faithfully determine their spatiotemporal distribution in cells. However, reliable multiplexing of knock-in events in neurons remains challenging because of cross talk between editing events. To overcome this, we developed conditional activation of knock-in expression (CAKE), allowing efficient, flexible, and accurate multiplex genome editing in rat neurons. To diminish cross talk, CAKE is based on sequential, recombinase-driven guide RNA (gRNA) expression to control the timing of genomic integration of each donor sequence. We show that CAKE is broadly applicable to co-label various endogenous proteins, including cytoskeletal proteins, synaptic scaffolds, ion channels and neurotransmitter receptor subunits. To take full advantage of CAKE, we resolved the nanoscale co-distribution of endogenous synaptic proteins using super-resolution microscopy, demonstrating that their co-organization depends on synapse size. Fi...