Cervical and trigeminal afferents innervate neighboring cranial territories, and their convergence on upper cervical dorsal horn neurons provides a potential substrate for pain referral in primary headache syndromes. Lamina I neurons are central to this mechanism, as they relay convergent nociceptive input to supraspinal pain centers. Unfortunately, little is known about the interactions between trigeminal and cervical afferents supplying Lamina I neurons. Here, we used rats of both sexes to show that cervical and trigeminal afferents interact via presynaptic inhibition, where monosynaptic inputs to Lamina I neurons undergo unidirectional as well as reciprocal presynaptic control. This means that afferent-driven presynaptic inhibition shapes the way trigeminal and cervical Aδ-fiber and C-fiber input reaches Lamina I projection neurons (PNs) and local-circuit neurons (LCNs). We propose that this inhibition provides a feedforward control of excitatory drive to Lamina I neurons that regulates their convergent...

Deactivation of G-protein-coupled receptors (GPCRs) involves multiple phosphorylations followed by arrestin binding, which uncouples the GPCR from G-protein activation. Some GPCRs, such as rhodopsin, are reused many times. Arrestin dissociation and GPCR dephosphorylation are key steps in the recycling process. In vitro evidence suggests that visual arrestin (ARR1) binding to light-activated, phosphorylated rhodopsin hinders dephosphorylation. Whether ARR1 binding also affects rhodopsin dephosphorylation in vivo is not known. We investigated this using both male and female mice lacking ARR1. Mice were exposed to bright light and placed in darkness for different periods of time, and differently phosphorylated species of rhodopsin were assayed by isoelectric focusing. For WT mice, rhodopsin dephosphorylation was nearly complete by 1 h in darkness. Surprisingly, we observed that, in the Arr1 KO rods, rhodopsin remained phosphorylated even after 3 h. Delayed dephosphorylation in Arr1 KO rods cannot be explained...

From an associative perspective the acquisition of new goal-directed actions requires the encoding of specific action-outcome (AO) associations and, therefore, sensitivity to the validity of an action as a predictor of a specific outcome relative to other events. Although competitive architectures have been proposed within associative learning theory to achieve this kind of identity-based selection, whether and how these architectures are implemented by the brain is still a matter of conjecture. To investigate this issue, we trained human participants to encode various AO associations while undergoing functional neuroimaging (fMRI). We then degraded one AO contingency by increasing the probability of the outcome in the absence of its associated action while keeping other AO contingencies intact. We found that this treatment selectively reduced performance of the degraded action. Furthermore, when a signal predicted the unpaired outcome, performance of the action was restored, suggesting that the degradatio...

Metacognition describes the process of monitoring one's own mental states, often for the purpose of cognitive control. Previous research has investigated how metacognitive signals are generated (metacognitive monitoring), for example, when people (both female/male) judge their confidence in their decisions and memories. Research has also investigated how metacognitive signals are used to influence behavior (metacognitive control), for example, setting a reminder (i.e., cognitive offloading) for something you are not confident you will remember. However, the mapping between metacognitive monitoring and metacognitive control needs further study on a neural level. We used fMRI to investigate a delayed-intentions task with a reminder element, allowing human participants to use their metacognitive insight to engage metacognitive control. Using multivariate pattern analysis, we found that we could separately decode both monitoring and control, and, to a lesser extent, cross-classify between them. Therefore, brai...

The mouse primary visual cortex is a model system for understanding the relationship between cortical structure, function, and behavior ([Seabrook et al., 2017][1]; [Chaplin and Margrie, 2020][2]; [Hooks and Chen, 2020][3]; [Saleem, 2020][4]; [Flossmann and Rochefort, 2021][5]). Binocular neurons in V1 are the cellular basis of binocular vision, which is required for predation ([Scholl et al., 2013][6]; [Hoy et al., 2016][7]; [La Chioma et al., 2020][8]; [Berson, 2021][9]; [Johnson et al., 2021][10]). The normal development of binocular responses, however, has not been systematically measured. Here, we measure tuning properties of neurons to either eye in awake mice of either sex from eye opening to the closure of the critical period. At eye opening, we find an adult-like fraction of neurons responding to the contralateral-eye stimulation, which are selective for orientation and spatial frequency; few neurons respond to ipsilateral eye, and their tuning is immature. Fraction of ipsilateral-eye responses in...

Yoshihiro Egashira, Ayane Kumade, Akio Ojida, and Fumihito Ono (see pages [3523–3536][1]) Axon terminals contain numerous synaptic vesicles. Vesicles docked at the presynaptic active zone are the first to fuse when the neuron begins to spike and are therefore called the readily releasable pool.

Decades of hippocampal neurophysiology research have linked the hippocampal theta rhythm to voluntary movement. A consistent observation has been a robust correlation between the amplitude (or power) and frequency of hippocampal theta and running speed. Recently, however, it has been suggested that acceleration, not running speed, is the dominating influence on theta frequency. There is an inherent interdependence among these two variables, as acceleration is the rate of change in velocity. Therefore, we investigated theta frequency and amplitude of the local-field potential recorded from the stratum pyramidale, stratum radiatum, and stratum lacunosum moleculare of the CA1 subregion, considering both speed and acceleration in tandem as animals traversed a circular task or performed continuous alternation. In male and female rats volitionally controlling their own running characteristics, we found that running speed carries nearly all of the variability in theta frequency and power, with a minute contributi...

Stimulus-specific adaptation (SSA) is the reduction in responses to frequent stimuli (standards) that does not generalize to rare stimuli (deviants). We investigated the contribution of inhibition in auditory cortex to SSA using two-photon targeted cell-attached recordings and optogenetic manipulations in male mice. We characterized the responses of PV-, SST-, and VIP-expressing interneurons of layer 2/3, and of serotonin receptor-expressing (HTR) interneurons of layer 1. All populations showed early-onset SSA. Unexpectedly, the PV, SST and VIP populations exhibited a substantial late component of evoked activity, often stronger for standard than for deviant stimuli. Optogenetic suppression of PV neurons facilitated pyramidal-neuron responses substantially more (∼x10) for deviants than for standards. VIP suppression decreased responses of putative PV neurons, specifically for standard but not for deviant stimuli. Thus, the inhibitory network does not generate cortical SSA, but powerfully controls its expre...

Hippocampal gamma and theta oscillations are associated with mnemonic and navigational processes and adapt to changes in an animal’s behavioral state to optimize spatial information processing. It has been shown that locomotor activity modulates gamma and theta frequencies in rats, although how age alters this modulation has not been well-studied. Here we examine gamma and theta local-field potential and place cell activity in the hippocampus CA1 region of young and old male rats as they performed a spatial eye-blink conditioning task across 31 days. While mean gamma frequency was similar in both groups, gamma frequency increased with running speed at a slower rate in old animals. By contrast, theta frequencies scaled with speed similarly in both groups, but were lower across speeds in old animals. While these frequencies scaled equally well with deceleration and speed, acceleration was less correlated with gamma frequency in both age groups. Additionally, spike phase-locking to gamma, but not theta, was g...

Learning is an essential cognitive mechanism allowing behavioral adaptation through adjustments in neuronal processing. It is associated with changes in the activity of sensory cortical neurons evoked by task-relevant stimuli. However, the exact nature of those modifications and the computational advantages they may confer are still debated. Here, we investigated how learning an orientation discrimination task alters the neuronal representations of the cues orientations in the primary visual cortex (V1) of male and female mice. When comparing the activity evoked by the task stimuli in naïve mice and mice performing the task, we found that the representations of the orientation of the rewarded and non-rewarded cues were more accurate and stable in trained mice. This better cue representation in trained mice was associated with a distortion of the orientation representation space such that stimuli flanking the task-relevant orientations were represented as the task stimuli themselves, suggesting that those s...