The fovea is a neural specialization that endows humans and other primates with the sharpest vision among mammals. This performance originates in the foveal cones, which are extremely narrow and long to form a high-resolution pixel array. Puzzlingly, this form is predicted to impede electrical conduction to an extent that appears incompatible with vision. We observe the opposite: signal flow through even the longest cones (0.4-mm axons) is essentially lossless. Unlike in most neurons, amplification and impulse generation by voltage-gated channels are dispensable. Rather, sparse channel activity preserves intracellular current, which flows as if unobstructed by organelles. Despite these optimizations, signaling would degrade if cones were lengthier. Because cellular packing requires that cone elongation accompanies foveal expansion, this degradation helps explain why the fovea is a constant, miniscule size despite multiplicative changes in eye size through evolution. These observations reveal how biophysical mechanisms tailor form-function relationships for primate behavioral performance.

The excitatory synapse between hippocampal CA3 and CA1 pyramidal neurons exhibits long-term potentiation (LTP), a positive feedback process implicated in learning and memory in which postsynaptic depolarization strengthens synapses, promoting further depolarization. Without mechanisms for interrupting positive feedback, excitatory synapses could strengthen inexorably, corrupting memory storage. Here, we reveal a hidden form of inhibitory synaptic plasticity that prevents accumulation of excitatory LTP. We developed a knockin mouse that allows optical control of endogenous α5-subunit-containing γ-aminobutyric acid (GABA)A receptors (α5-GABARs). Induction of excitatory LTP relocates α5-GABARs, which are ordinarily extrasynaptic, to inhibitory synapses, quashing further NMDA receptor activation necessary for inducing more excitatory LTP. Blockade of α5-GABARs accelerates reversal learning, a behavioral test for cognitive flexibility dependent on repeated LTP. Hence, inhibitory synaptic plasticity occurs in parallel with excitatory synaptic plasticity, with the ensuing interruption of the positive feedback cycle of LTP serving as a possible critical early step in preserving memory.

Nicotine stimulates dopamine (DA) neurons of the ventral tegmental area (VTA) to establish and maintain reinforcement. Nicotine also induces anxiety through an as yet unknown circuitry. We found that nicotine injection drives opposite functional responses of two distinct populations of VTA DA neurons with anatomically segregated projections: it activates neurons that project to the nucleus accumbens (NAc), whereas it inhibits neurons that project to the amygdala nuclei (Amg). We further show that nicotine mediates anxiety-like behavior by acting on β2-subunit-containing nicotinic acetylcholine receptors of the VTA. Finally, using optogenetics, we bidirectionally manipulate the VTA-NAc and VTA-Amg pathways to dissociate their contributions to anxiety-like behavior. We show that inhibition of VTA-Amg DA neurons mediates anxiety-like behavior, while their activation prevents the anxiogenic effects of nicotine. These distinct subpopulations of VTA DA neurons with opposite responses to nicotine may differentially drive the anxiogenic and the reinforcing effects of nicotine.

Interoception, the sense of internal bodily signals, is essential for physiological homeostasis, cognition, and emotions. While human insular cortex (InsCtx) is implicated in interoception, the cellular and circuit mechanisms remain unclear. We imaged mouse InsCtx neurons during two physiological deficiency states: hunger and thirst. InsCtx ongoing activity patterns reliably tracked the gradual return to homeostasis but not changes in behavior. Accordingly, while artificial induction of hunger or thirst in sated mice via activation of specific hypothalamic neurons (AgRP or SFOGLUT) restored cue-evoked food- or water-seeking, InsCtx ongoing activity continued to reflect physiological satiety. During natural hunger or thirst, food or water cues rapidly and transiently shifted InsCtx population activity to the future satiety-related pattern. During artificial hunger or thirst, food or water cues further shifted activity beyond the current satiety-related pattern. Together with circuit-mapping experiments, these findings suggest that InsCtx integrates visceral-sensory signals of current physiological state with hypothalamus-gated amygdala inputs that signal upcoming ingestion of food or water to compute a prediction of future physiological state.

Female mice exhibit opposing social behaviors toward males depending on their reproductive state: virgins display sexual receptivity (lordosis behavior), while lactating mothers attack. How a change in reproductive state produces a qualitative switch in behavioral response to the same conspecific stimulus is unknown. Using single-cell RNA-seq, we identify two distinct subtypes of estrogen receptor-1-positive neurons in the ventrolateral subdivision of the female ventromedial hypothalamus (VMHvl) and demonstrate that they causally control sexual receptivity and aggressiveness in virgins and lactating mothers, respectively. Between- and within-subject bulk-calcium recordings from each subtype reveal that aggression-specific cells acquire an increased responsiveness to social cues during the transition from virginity to maternity, while the responsiveness of the mating-specific population appears unchanged. These results demonstrate that reproductive-state-dependent changes in the relative activity of transcriptomically distinct neural subtypes can underlie categorical switches in behavior associated with physiological state changes.

Dendritic spines are the major transmitter reception compartments of glutamatergic synapses in most principal neurons of the mammalian brain and play a key role in the function of nerve cell circuits. The formation of functional spine synapses is thought to be critically dependent on presynaptic glutamatergic signaling. By analyzing CA1 pyramidal neurons in mutant hippocampal slice cultures that are essentially devoid of presynaptic transmitter release, we demonstrate that the formation and maintenance of dendrites and functional spines are independent of synaptic glutamate release.

The abundance of presynaptic CaV2 voltage-gated Ca2+ channels (CaV2) at mammalian active zones (AZs) regulates the efficacy of synaptic transmission. It is proposed that presynaptic CaV2 levels are saturated in AZs due to a finite number of slots that set CaV2 subtype abundance and that CaV2.1 cannot compete for CaV2.2 slots. However, at most AZs, CaV2.1 levels are highest and CaV2.2 levels are developmentally reduced. To investigate CaV2.1 saturation states and preference in AZs, we overexpressed the CaV2.1 and CaV2.2 α1 subunits at the calyx of Held at immature and mature developmental stages. We found that AZs prefer CaV2.1 to CaV2.2. Remarkably, CaV2.1 α1 subunit overexpression drove increased CaV2.1 currents and channel numbers and increased synaptic strength at both developmental stages examined. Therefore, we propose that CaV2.1 levels in the AZ are not saturated and that synaptic strength can be modulated by increasing CaV2.1 levels to regulate neuronal circuit output. VIDEO ABSTRACT.

Animals depend on sensory feedback from mechanosensory afferents for the dynamic control of movement. This sensory feedback needs to be selectively modulated in a task- and context-dependent manner. Here, we show that inhibitory interneurons (INs) expressing the RORβ orphan nuclear receptor gate sensory feedback to the spinal motor system during walking and are required for the production of a fluid locomotor rhythm. Genetic manipulations that abrogate inhibitory RORβ IN function result in an ataxic gait characterized by exaggerated flexion movements and marked alterations to the step cycle. Inactivation of RORβ in inhibitory neurons leads to reduced presynaptic inhibition and changes to sensory-evoked reflexes, arguing that the RORβ inhibitory INs function to suppress the sensory transmission pathways that activate flexor motor reflexes and interfere with the ongoing locomotor program. VIDEO ABSTRACT.

Basal ganglia play a central role in regulating behavior, but the organization of their outputs to other brain areas is incompletely understood. We investigate the largest output nucleus, the substantia nigra pars reticulata (SNr), and delineate the organization and physiology of its projection populations in mice. Using genetically targeted viral tracing and whole-brain anatomical analysis, we identify over 40 SNr targets that encompass a roughly 50-fold range of axonal densities. Retrograde tracing from the volumetrically largest targets indicates that the SNr contains segregated subpopulations that differentially project to functionally distinct brain stem regions. These subpopulations are electrophysiologically specialized and topographically organized and collateralize to common diencephalon targets, including the motor and intralaminar thalamus as well as the pedunculopontine nucleus and the midbrain reticular formation. These findings establish that SNr signaling is organized as dense, parallel outputs to specific brain stem targets concurrent with extensive collateral branches that encompass the majority of SNr axonal boutons.

The mammalian genome has hundreds of nuclear-encoded tRNAs, but the contribution of individual tRNA genes to cellular and organismal function remains unknown. Here, we demonstrate that mutations in a neuronally enriched arginine tRNA, n-Tr20, increased seizure threshold and altered synaptic transmission. n-Tr20 expression also modulated seizures caused by an epilepsy-linked mutation in Gabrg2, a gene encoding a GABAA receptor subunit. Loss of n-Tr20 altered translation initiation by activating the integrated stress response and suppressing mTOR signaling, the latter of which may contribute to altered neurotransmission in mutant mice. Deletion of a highly expressed isoleucine tRNA similarly altered these signaling pathways in the brain, suggesting that regulation of translation initiation is a conserved response to tRNA loss. Our data indicate that loss of a single member of a tRNA family results in multiple cellular phenotypes, highlighting the disease-causing potential of tRNA mutations.

Oligodendrocyte progenitor cells (OPCs), which differentiate into myelinating oligodendrocytes during CNS development, are the main proliferative cells in the adult brain. OPCs are conventionally considered a homogeneous population, particularly with respect to their electrophysiological properties, but this has been debated. We show, by using single-cell electrophysiological recordings, that OPCs start out as a homogeneous population but become functionally heterogeneous, varying both within and between brain regions and with age. These electrophysiological changes in OPCs correlate with the differentiation potential of OPCs; thus, they may underlie the differentiational differences in OPCs between regions and, likewise, differentiation failure with age.