The exquisite capacity of primates to detect and recognize faces is crucial for social interactions. Although disentangling the neural basis of human face recognition remains a key goal in neuroscience, direct evidence at the single-neuron level is limited. We recorded from face-selective neurons in human visual cortex in a region characterized by functional magnetic resonance imaging (fMRI) activations for faces compared with objects. The majority of visually responsive neurons in this fMRI activation showed strong selectivity at short latencies for faces compared with objects. Feature-scrambled faces and face-like objects could also drive these neurons, suggesting that this region is not tightly tuned to the visual attributes that typically define whole human faces. These single-cell recordings within the human face processing system provide vital experimental evidence linking previous imaging studies in humans and invasive studies in animal models. Significance Statement We present the first recordin...

Loss-of-function mutations in endosomal Na+/H+ exchanger 6 (NHE6) cause the X-linked neurologic disorder Christianson syndrome. Patients exhibit symptoms associated with both neurodevelopmental and neurodegenerative abnormalities. While loss of NHE6 has been shown to overacidify the endosome lumen, and is associated with endolysosome neuropathology, NHE6-mediated mechanisms in endosome trafficking and lysosome function have been understudied. Here, we show that NHE6-null mouse neurons demonstrate worsening lysosome function with time in culture, likely as a result of defective endosome trafficking. NHE6-null neurons exhibit overall reduced lysosomal proteolysis despite overacidification of the endosome and lysosome lumen. Akin to Nhx1 mutants in Saccharomyces cerevisiae , we observe decreased endosome-lysosome fusion in NHE6-null neurons. Also, we find premature activation of pH-dependent cathepsin D (CatD) in endosomes. While active CatD is increased in endosomes, CatD activation and CatD protein levels a...

In contrast to easily formed fear memories, fear extinction requires prolonged training. The prelimbic cortex (PL), which integrates signals from brain structures involved in fear conditioning and extinction such as the ventral hippocampus (vHIP) and the basolateral amygdala (BL), is necessary for fear memory retrieval. Little is known, however, about how the vHIP and BL inputs to the PL regulate the display of fear after fear extinction. Using functional anatomy tracing in male rats, we found two distinct subpopulations of neurons in the PL activated by either the successful extinction or the relapse of fear. During the retrieval of fear extinction memory, the dominant input to active neurons in the PL was from the vHIP, whereas the retrieval of fear memory, regardless of the age of a memory and testing context, was associated with greater BL input. Optogenetic stimulation of the vHIP–PL pathway after one session of fear extinction increased conditioned fear, whereas stimulation of the vHIP inputs after s...

Amrita Benoy, Mohammad Zaki Bin Ibrahim, Thomas Behnisch, and Sreedharan Sajikumar (see pages [9082–9098][1]) Studies of hippocampal function have focused overwhelmingly on areas CA1, CA3, and the dentate gyrus, largely ignoring CA2. Yet recent work has revealed several intriguing features of

Hippocampal CA2, an inconspicuously positioned area between the well-studied CA1 and CA3 subfields, has captured research interest in recent years because of its role in social memory formation. However, the role of cholinergic inputs to the CA2 area for the regulation of synaptic plasticity remains to be fully understood. We show that cholinergic receptor activation with the nonselective cholinergic agonist, carbachol (CCh), triggers a protein synthesis-dependent and NMDAR-independent long-term synaptic depression (CCh-LTD) at entorhinal cortical (EC)-CA2 and Schaffer collateral (SC)-CA2 synapses in the hippocampus of adult male Wistar rats. The activation of muscarinic acetylcholine receptors (mAChRs) is critical for the induction of CCh-LTD with the results suggesting an involvement of M3 and M1 mAChRs in the early facilitation of CCh-LTD, while nicotinic AChR activation plays a role in the late maintenance of CCh-LTD at CA2 synapses. Remarkably, we find that CCh priming lowers the threshold for the sub...

How does the brain integrate signals with different timescales to drive purposeful actions? Brain-machine interfaces (BMIs) offer a powerful tool to causally test how distributed neural networks achieve specific neural patterns. During neuroprosthetic learning, actuator movements are causally linked to primary motor cortex (M1) neurons - i.e., “direct” neurons that project to the decoder and whose firing is required to successfully perform the task. However, it is unknown how such direct M1 neurons interact with both “indirect” local (in M1 but not part of the decoder) and across area neural populations (e.g., in premotor cortex/M2), all of which are embedded in complex biological recurrent networks. Here, we trained male rats to perform a M1-BMI task and simultaneously recorded the activity of indirect neurons in both M2 and M1. We found that both M2 and M1 indirect neuron populations could be used to predict the activity of the direct neurons (i.e., “BMI-potent activity”). Interestingly, compared to M1 i...

Aging is associated with cognitive impairment, but there are large individual differences in these declines. One neural measure that is lower in older adults and predicts these individual differences is moment-to-moment brain signal variability. Testing the assumption that GABA should heighten neural variability, we examined whether reduced brain signal variability in older, poorer performing adults could be boosted by increasing GABA pharmacologically. Brain signal variability was estimated using fMRI in 20 young and 24 older healthy human adults during placebo and GABA agonist sessions. As expected, older adults exhibited lower signal variability at placebo, and, crucially, GABA agonism boosted older adults’ variability to the levels of young adults. Furthermore, poorer performing older adults experienced a greater increase in variability on drug, suggesting that those with more to gain benefit the most from GABA system potentiation. GABA may thus serve as a core neurochemical target in future work on ag...

Attention often requires maintaining a stable mental state over time while simultaneously improving perceptual sensitivity. These requirements place conflicting demands on neural populations, as sensitivity implies a robust response to perturbation by incoming stimuli, which is antithetical to stability. Functional specialization of cortical areas provides one potential mechanism to resolve this conflict. We reasoned that attention signals in executive control areas might be highly stable over time, reflecting maintenance of the cognitive state, thereby freeing up sensory areas to be more sensitive to sensory input (i.e., unstable), which would be reflected by more dynamic attention signals in those areas. To test these predictions, we simultaneously recorded neural populations in prefrontal cortex (PFC) and visual cortical area V4 in rhesus macaque monkeys performing an endogenous spatial selective attention task. Using a decoding approach, we found that the neural code for attention states in PFC was sub...

The basolateral amygdala (BLA) is obligatory for fear learning. This learning is linked to BLA excitatory projection neurons whose activity is regulated by complex networks of inhibitory interneurons, dominated by parvalbumin (PV)-expressing GABAergic neurons. The roles of these GABAergic interneurons in learning to fear and learning not to fear, activity profiles of these interneurons across the course of fear learning, and whether or how these change across the course of learning all remain poorly understood. Here, we used PV cell-type-specific recording and manipulation approaches in male transgenic PV-Cre rats during pavlovian fear conditioning to address these issues. We show that activity of BLA PV neurons during the moments of aversive reinforcement controls fear learning about aversive events, but activity during moments of nonreinforcement does not control fear extinction learning. Furthermore, we show expectation-modulation of BLA PV neurons during fear learning, with greater activity to an unexp...