A Critical Role for Neocortical Processing of Threat Memory.

Memory of cues associated with threat is critical for survival and a leading model for elucidating how sensory information is linked to adaptive behavior by learning. Although the brain-wide circuits mediating auditory threat memory have been intensely investigated, it remains unclear whether the auditory cortex is critically involved. Here we use optogenetic activity manipulations in defined cortical areas and output pathways, viral tracing, pathway-specific in vivo 2-photon calcium imaging, and computational analyses of population plasticity to reveal that the auditory cortex is selectively required for conditioning to complex stimuli, whereas the adjacent temporal association cortex controls all forms of auditory threat memory. More temporal areas have a stronger effect on memory and more neurons projecting to the lateral amygdala, which control memory to complex stimuli through a balanced form of population plasticity that selectively supports discrimination of significant sensory stimuli. Thus, neocortical processing plays a critical role in cued threat memory.

Disinhibition Goes Spatial.

Memorizing significant locations in the environment is a fundamental capacity of the brain. In this issue, Turi et al. (2019) present multidisciplinary evidence for a critical involvement of disinhibitory interneurons in hippocampal CA1 in this process.

Learning-Related Plasticity in Dendrite-Targeting Layer 1 Interneurons.

A wealth of data has elucidated the mechanisms by which sensory inputs are encoded in the neocortex, but how these processes are regulated by the behavioral relevance of sensory information is less understood. Here, we focus on neocortical layer 1 (L1), a key location for processing of such top-down information. Using Neuron-Derived Neurotrophic Factor (NDNF) as a selective marker of L1 interneurons (INs) and in vivo 2-photon calcium imaging, electrophysiology, viral tracing, optogenetics, and associative memory, we find that L1 NDNF-INs mediate a prolonged form of inhibition in distal pyramidal neuron dendrites that correlates with the strength of the memory trace. Conversely, inhibition from Martinotti cells remains unchanged after conditioning but in turn tightly controls sensory responses in NDNF-INs. These results define a genetically addressable form of dendritic inhibition that is highly experience dependent and indicate that in addition to disinhibition, salient stimuli are encoded at elevated levels of distal dendritic inhibition. VIDEO ABSTRACT.

Intact neuronal function in Rheb1 mutant mice: implications for TORC1-based treatments.

Target of rapamycin complex 1 (TORC1) is an important regulator of neuronal function. However, whereas a modest activation of the TORC1 signaling pathway has been shown to affect synaptic plasticity, learning and memory, the effect of TORC1 hypo-activation is less clear. This knowledge is particularly important since TORC1 inhibitors may hold great promise for treating a variety of disorders, including developmental disorders, aging-related disorders, epilepsy and cancer. Such treatments are likely to be long lasting and could involve treating young children. Hence, it is pivotal that the effects of sustained TORC1 inhibition on brain development and cognitive function are determined. Here, we made use of constitutive and conditional Rheb1 mutant mice to study the effect of prolonged and specific reduction in the TORC1 pathway. We show that Rheb1 mutant mice show up to 75% reduction in TORC1 signaling, but develop normally and show intact synaptic plasticity and hippocampus-dependent learning and memory. We discuss our findings in light of current literature in which the effect of pharmacological inhibition of TORC1 is studied in the context of synaptic plasticity and learning. We conclude that in contrast to TORC1 hyper-activity, cognitive function is not very sensitive to sustained and specific down-regulation of TORC1 activity.

TORC1-dependent epilepsy caused by acute biallelic Tsc1 deletion in adult mice.

OBJECTIVE: Seizure development in tuberous sclerosis complex (TSC) correlates with the presence of specific lesions called cortical tubers. Moreover, heterozygous TSC animal models do not show gross brain pathology and are seizure-free, suggesting that such pathology is a prerequisite for the development of epilepsy. However, cells within TSC lesions show increased activity of the target of rapamycin complex 1 (TORC1) pathway, and recent studies have implicated this pathway in non-TSC-related animal models of epilepsy and neuronal excitability. These findings imply a direct role for TORC1 in epilepsy. Here, we investigate the effect of increased TORC1 signaling induced by acute biallelic deletion of Tsc1 in healthy adult mice. METHODS: Biallelic Tsc1 gene deletion was induced in adult Tsc1 heterozygous and wild-type mice. Seizures were monitored by electroencephalographic and video recordings. Molecular and cellular changes were investigated by Western blot analysis, immunohistochemistry, and electrophysiology. RESULTS: Mice developed epilepsy a few days after biallelic Tsc1 deletion. Acute gene deletion was not accompanied by any obvious histological changes, but resulted in activation of the TORC1 pathway, enhanced neuronal excitability, and a decreased threshold for protein-synthesis-dependent long-term potentiation preceding the onset of seizures. Rapamycin treatment after seizure onset reduced TORC1 activity and fully abolished the seizures. INTERPRETATION: Our data indicate a direct role for TORC1 signaling in epilepsy development, even in the absence of major brain pathology. This suggests that TORC1 is a promising target for treating seizures not only in TSC but also in other forms of epilepsy that result from increased TORC1 activation.