To study how the interaction between orbitofrontal (OFC) and rhinal (Rh) cortices influences the judgment of reward size, we reversibly disconnected these regions using hM4Di-DREADD (designer ...receptor exclusively activated by designer drug). Repeated inactivation reduced sensitivity to differences in reward size in two monkeys. These results suggest that retrieval of relative stimulus values from memory depends on the interaction between Rh and OFC.
Decades of neuroscientific research has sought to understand medial temporal lobe (MTL) involvement in perception. Apparent inconsistencies in the literature have led to competing interpretations of ...the available evidence; critically, findings from human participants with naturally occurring MTL damage appear to be inconsistent with data from monkeys with surgical lesions. Here, we leverage a 'stimulus-computable' proxy for the primate ventral visual stream (VVS), which enables us to formally evaluate perceptual demands across stimulus sets, experiments, and species. With this modeling framework, we analyze a series of experiments administered to monkeys with surgical, bilateral damage to perirhinal cortex (PRC), an MTL structure implicated in visual object perception. Across experiments, PRC-lesioned subjects showed no impairment on perceptual tasks; this originally led us(Eldridge et al., 2018) to conclude that PRC is not involved in perception. Here, we find that a 'VVS-like' model predicts both PRC-intact and -lesioned choice behaviors, suggesting that a linear readout of the VVS should be sufficient for performance on these tasks. Evaluating these computational results alongside findings from human experiments, we suggest that results from (Eldridge et al., 2018) alone cannot be used as evidence against PRC involvement in perception. These data indicate that experimental findings from human and non-human primates are consistent. As such, what appeared to be discrepancies between species was in fact due to reliance on informal accounts of perceptual processing.
Artificial activation of neurons in early visual areas induces perception of simple visual flashes.1,2 Accordingly, stimulation in high-level visual cortices is expected to induce perception of ...complex features.3,4 However, results from studies in human patients challenge this expectation. Stimulation rarely induces any detectable visual event, and never a complex one, in human subjects with closed eyes.2 Stimulation of the face-selective cortex in a human patient led to remarkable hallucinations only while the subject was looking at faces.5 In contrast, stimulations of color- and face-selective sites evoke notable hallucinations independent of the object being viewed.6 These anecdotal observations suggest that stimulation of high-level visual cortex can evoke perception of complex visual features, but these effects depend on the availability and content of visual input. In this study, we introduce a novel psychophysical task to systematically investigate characteristics of the perceptual events evoked by optogenetic stimulation of macaque inferior temporal (IT) cortex. We trained macaque monkeys to detect and report optogenetic impulses delivered to their IT cortices7,8,9 while holding fixation on object images. In a series of experiments, we show that detection of cortical stimulation is highly dependent on the choice of images presented to the eyes and it is most difficult when fixating on a blank screen. These findings suggest that optogenetic stimulation of high-level visual cortex results in easily detectable distortions of the concurrent contents of vision.
•Monkeys learn to reliably detect optogenetic stimulation in inferotemporal cortex•Behavioral detection of cortical stimulation depends on the image being viewed•Cortical stimulation is the least perceivable in the absence of visual stimulus
Azadi et al. find that perception of cortical stimulation in the inferior temporal cortex depends on the choice and visibility of images presented to the eyes at the time of stimulation, and it is the least perceivable when no image was presented. This suggests that the physiological effect of local stimulation varies with the state of vision.
Transmission from striatal cholinergic interneurons (CINs) controls dopamine release through nicotinic acetylcholine receptors (nAChRs) on dopaminergic axons. Anatomical studies suggest that ...cholinergic terminals signal predominantly through non-synaptic volume transmission. However, the influence of cholinergic transmission on electrical signaling in axons remains unclear. We examined axo-axonal transmission from CINs onto dopaminergic axons using perforated-patch recordings, which revealed rapid spontaneous EPSPs with properties characteristic of fast synapses. Pharmacology showed that axonal EPSPs (axEPSPs) were mediated primarily by high-affinity α6-containing receptors. Remarkably, axEPSPs triggered spontaneous action potentials, suggesting that these axons perform integration to convert synaptic input into spiking, a function associated with somatodendritic compartments. We investigated the cross-species validity of cholinergic axo-axonal transmission by recording dopaminergic axons in macaque putamen and found similar axEPSPs. Thus, we reveal that synaptic-like neurotransmission underlies cholinergic signaling onto dopaminergic axons, supporting the idea that striatal dopamine release can occur independently of somatic firing to provide distinct signaling.
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•Cholinergic interneurons signal to DA axons with phasic axonal EPSPs (axEPSPs)•AxEPSPs have many characteristics similar to synaptic depolarizations•Spontaneous axEPSPs can evoke spontaneous action potentials locally in the axon•AxEPSPs shape input-output function of DA axons, distinct from somatic signaling
Dopaminergic axons express nicotinic receptors that modulate and evoke neurotransmitter release. Using direct recordings from dopaminergic axons, Kramer et al. reveal the presence of spontaneous synaptic-like nicotinic axonal EPSPs capable of generating spontaneous axonal action potentials. These findings demonstrate the mechanisms underlying nicotinic-receptor-mediated membrane-potential signaling in dopaminergic axons.
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for ...human applications as well. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated
F positron emission tomography (PET) DREADD radiotracer,
FJHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency.
FJHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping.
Previous work found that 11Cdeschloroclozapine (11CDCZ) is superior to 11Cclozapine (11CCLZ) for imaging Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). This study used PET to ...quantitatively and separately measure the signal from transfected receptors, endogenous receptors/targets, and non-displaceable binding in other brain regions to better understand this superiority. A genetically-modified muscarinic type-4 human receptor (hM4Di) was injected into the right amygdala of a male rhesus macaque. 11CDCZ and 11CCLZ PET scans were conducted 2–24 months later. Uptake was quantified relative to the concentration of parent radioligand in arterial plasma at baseline (n = 3 scans/radioligand) and after receptor blockade (n = 3 scans/radioligand). Both radioligands had greater uptake in the transfected region and displaceable uptake in other brain regions. Displaceable uptake was not uniformly distributed, perhaps representing off-target binding to endogenous receptor(s). After correction, 11CDCZ signal was 19% of that for 11CCLZ, and background uptake was 10% of that for 11CCLZ. Despite stronger 11CCLZ binding, the signal-to-background ratio for 11CDCZ was almost two-fold greater than for 11CCLZ. Both radioligands had comparable DREADD selectivity. All reference tissue models underestimated signal-to-background ratio in the transfected region by 40%–50% for both radioligands. Thus, the greater signal-to-background ratio of 11CDCZ was due to its lower background uptake.
The rostromedial caudate (rmCD) of primates is thought to contribute to reward value processing, but a causal relationship has not been established. Here we use an inhibitory DREADD (Designer ...Receptor Exclusively Activated by Designer Drug) to repeatedly and non-invasively inactivate rmCD of macaque monkeys. We inject an adeno-associated viral vector expressing the inhibitory DREADD, hM4Di, into the rmCD bilaterally. To visualize DREADD expression in vivo, we develop a non-invasive imaging method using positron emission tomography (PET). PET imaging provides information critical for successful chemogenetic silencing during experiments, in this case the location and level of hM4Di expression, and the relationship between agonist dose and hM4Di receptor occupancy. Here we demonstrate that inactivating bilateral rmCD through activation of hM4Di produces a significant and reproducible loss of sensitivity to reward value in monkeys. Thus, the rmCD is involved in making normal judgments about the value of reward.
Abstract
Chemogenetic tools are designed to control neuronal signaling. These tools have the potential to contribute to the understanding of neuropsychiatric disorders and to the development of new ...treatments. One such chemogenetic technology comprises modified Pharmacologically Selective Actuator Modules (PSAMs) paired with Pharmacologically Selective Effector Molecules (PSEMs). PSAMs are receptors with ligand-binding domains that have been modified to interact only with a specific small-molecule agonist, designated a PSEM. PSAM
4
is a triple mutant PSAM derived from the α7 nicotinic receptor (α7
L131G,Q139L,Y217F
). Although having no constitutive activity as a ligand-gated ion channel, PSAM
4
has been coupled to the serotonin 5-HT
3
receptor (5-HT
3
R) and to the glycine receptor (GlyR). Treatment with the partner PSEM to activate PSAM
4
-5-HT
3
or PSAM
4
-GlyR, causes neuronal activation or silencing, respectively. A suitably designed radioligand may enable selective visualization of the expression and location of PSAMs with positron emission tomography (PET). Here, we evaluated uPSEM792, an ultrapotent PSEM for PSAM
4
-GlyR, as a possible lead for PET radioligand development. We labeled uPSEM792 with the positron-emitter, carbon-11 (
t
1/2
= 20.4 min), in high radiochemical yield by treating a protected precursor with
11
Ciodomethane followed by base deprotection. PET experiments with
11
CuPSEM792 in rodents and in a monkey transduced with PSAM
4
-GlyR showed low peak radioactivity uptake in brain. This low uptake was probably due to high polarity of the radioligand, as evidenced by physicochemical measurements, and to the vulnerability of the radioligand to efflux transport at the blood–brain barrier. These findings can inform the design of a more effective PSAM
4
based PET radioligand, based on the uPSEM792 chemotype.
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![[11C]deschloroclozapine is ...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0271-678X_1559-7016/small "[11C]deschloroclozapine is an improved PET radioligand for quantifying a human muscarinic DREADD expressed in monkey brain")
