Although a wealth of data have elucidated the structure and physiology of neuronal circuits, we still only have a very limited understanding of how behavioral learning is implemented at the network ...level. An emerging crucial player in this implementation is disinhibition—a transient break in the balance of excitation and inhibition. In contrast to the widely held view that the excitation/inhibition balance is highly stereotyped in cortical circuits, recent findings from behaving animals demonstrate that salient events often elicit disinhibition of projection neurons that favors excitation and thereby enhances their activity. Behavioral functions ranging from auditory fear learning, for which most data are available to date, to spatial navigation are causally linked to disinhibition in different compartments of projection neurons, in diverse cortical areas and at timescales ranging from milliseconds to days, suggesting that disinhibition is a conserved circuit mechanism contributing to learning and memory expression.
Letzkus, Wolff and Lüthi review emerging evidence suggesting that disinhibition—a transient reduction of synaptic inhibition—is a conserved circuit mechanism in cortex that controls learning, memory expression and the plasticity state of the network.
Memories are acquired and encoded within large-scale neuronal networks spanning different brain areas. The anatomical and functional specificity of such long-range interactions and their role in ...learning is poorly understood. The amygdala and the medial prefrontal cortex (mPFC) are interconnected brain structures involved in the extinction of conditioned fear. Here, we show that a defined subpopulation of basal amygdala (BA) projection neurons targeting the prelimbic (PL) subdivision of mPFC is active during states of high fear, whereas BA neurons targeting the infralimbic (IL) subdivision are recruited, and exhibit cell-type-specific plasticity, during fear extinction. Pathway-specific optogenetic manipulations demonstrate that the activity balance between pathways is causally involved in fear extinction. Together, our findings demonstrate that, although intermingled locally, long-range connectivity defines distinct subpopulations of amygdala projection neurons and indicate that the formation of long-term extinction memories depends on the balance of activity between two defined amygdala-prefrontal pathways.
Learning causes a change in how information is processed by neuronal circuits. Whereas synaptic plasticity, an important cellular mechanism, has been studied in great detail, we know much less about ...how learning is implemented at the level of neuronal circuits and, in particular, how interactions between distinct types of neurons within local networks contribute to the process of learning. Here we show that acquisition of associative fear memories depends on the recruitment of a disinhibitory microcircuit in the mouse auditory cortex. Fear-conditioning-associated disinhibition in auditory cortex is driven by foot-shock-mediated cholinergic activation of layer 1 interneurons, in turn generating inhibition of layer 2/3 parvalbumin-positive interneurons. Importantly, pharmacological or optogenetic block of pyramidal neuron disinhibition abolishes fear learning. Together, these data demonstrate that stimulus convergence in the auditory cortex is necessary for associative fear learning to complex tones, define the circuit elements mediating this convergence and suggest that layer-1-mediated disinhibition is an important mechanism underlying learning and information processing in neocortical circuits.
Optogenetics revolutionizes basic research in neuroscience and cell biology and bears potential for medical applications. We develop mutants leading to a unifying concept for the construction of ...various channelrhodopsins with fast closing kinetics. Due to different absorption maxima these channelrhodopsins allow fast neural photoactivation over the whole range of the visible spectrum. We focus our functional analysis on the fast-switching, red light-activated Chrimson variants, because red light has lower light scattering and marginal phototoxicity in tissues. We show paradigmatically for neurons of the cerebral cortex and the auditory nerve that the fast Chrimson mutants enable neural stimulation with firing frequencies of several hundred Hz. They drive spiking at high rates and temporal fidelity with low thresholds for stimulus intensity and duration. Optical cochlear implants restore auditory nerve activity in deaf mice. This demonstrates that the mutants facilitate neuroscience research and future medical applications such as hearing restoration.
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.
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•NDNF is a selective marker for neocortical layer 1 interneurons•NDNF interneurons mediate prolonged inhibition of distal pyramidal neuron dendrites•Inhibition from Martinotti cells tightly controls NDNF interneuron responses•Dendritic inhibition by NDNF interneurons is highly experience dependent
Using a selective marker for neocortical layer 1 interneurons, Abs, Poorthuis, et al. identify these little-understood cells as a powerful, highly experience-dependent source of inhibition in pyramidal neuron dendrites that is in turn controlled by activity in the local circuit.
•Layer 1 is a central locus of neocortical associations controlled by two distinct types of inhibition.•Both types of inhibition control calcium spikes in apical tuft dendrites of pyramidal ...neurons.•Layer 1-targeting Martinotti cells undergo and instruct plasticity in a variety of learning contexts.•Layer 1 interneurons, for which a selective marker recently been identified, play a major role in associative learning.•Despite similarities, the two cell types may play different, potentially opposing roles in circuit plasticity.
Neocortical layer 1 is a major site of convergence for a variety of brain wide afferents carrying experience-dependent top-down information, which are integrated and processed in the apical tuft dendrites of pyramidal cells. Two types of local inhibitory interneurons, Martinotti cells and layer 1 interneurons, dominantly shape dendritic integration, and work from recent years has significantly advanced our understanding of the role of these interneurons in circuit plasticity and learning. Both cell types instruct plasticity in local pyramidal cells, and are themselves subject to robust plastic changes. Despite these similarities, the emerging hypothesis is that they fulfill different, and potentially opposite roles, as they receive different inputs, employ distinct inhibitory dynamics and are implicated in different behavioral contexts.
Neuronal circuits of fear extinction Herry, Cyril; Ferraguti, Francesco; Singewald, Nicolas ...
The European journal of neuroscience,
02/2010, Letnik:
31, Številka:
4
Journal Article
Recenzirano
Fear extinction is a form of inhibitory learning that allows for the adaptive control of conditioned fear responses. Although fear extinction is an active learning process that eventually leads to ...the formation of a consolidated extinction memory, it is a fragile behavioural state. Fear responses can recover spontaneously or subsequent to environmental influences, such as context changes or stress. Understanding the neuronal substrates of fear extinction is of tremendous clinical relevance, as extinction is the cornerstone of psychological therapy of several anxiety disorders and because the relapse of maladaptative fear and anxiety is a major clinical problem. Recent research has begun to shed light on the molecular and cellular processes underlying fear extinction. In particular, the acquisition, consolidation and expression of extinction memories are thought to be mediated by highly specific neuronal circuits embedded in a large‐scale brain network including the amygdala, prefrontal cortex, hippocampus and brain stem. Moreover, recent findings indicate that the neuronal circuitry of extinction is developmentally regulated. Here, we review emerging concepts of the neuronal circuitry of fear extinction, and highlight novel findings suggesting that the fragile phenomenon of extinction can be converted into a permanent erasure of fear memories. Finally, we discuss how research on genetic animal models of impaired extinction can further our understanding of the molecular and genetic bases of human anxiety disorders.
A neuropeptide making memories Schroeder, Anna; Letzkus, Johannes J.
Cell,
10/2021, Letnik:
184, Številka:
22
Journal Article
Recenzirano
Neuropeptides are the most diverse class of signaling molecules in the brain. Despite evidence for their involvement in several behavioral functions, the precise circuit elements and neuronal ...computations they control remain elusive. In this issue, Melzer et al. (2021) reveal how the neuropeptide GRP facilitates memory in the neocortex.
Neuropeptides are the most diverse class of signaling molecules in the brain. Despite evidence for their involvement in several behavioral functions, the precise circuit elements and neuronal computations they control remain elusive. In this issue, Melzer et al. (2021) reveal how the neuropeptide GRP facilitates memory in the neocortex.
Probing top-down information in neocortical layer 1 Pardi, M. Belén; Schroeder, Anna; Letzkus, Johannes J.
Trends in neurosciences (Regular ed.),
January 2023, 2023-Jan, 2023-01-00, 20230101, Letnik:
46, Številka:
1
Journal Article
Recenzirano
Accurate perception of the environment is a constructive process that requires integration of external bottom-up sensory signals with internally generated top-down information. Decades of work have ...elucidated how sensory neocortex processes physical stimulus features. By contrast, examining how top-down information is encoded and integrated with bottom-up signals has been challenging using traditional neuroscience methods. Recent technological advances in functional imaging of brain-wide afferents in behaving mice have enabled the direct measurement of top-down information. Here, we review the emerging literature on encoding of these internally generated signals by different projection systems enriched in neocortical layer 1 during defined brain functions, including memory, attention, and predictive coding. Moreover, we identify gaps in current knowledge and highlight future directions for this rapidly advancing field.
Higher brain functions critically depend on top-down projections that are strongly enriched in the outermost layer 1 of the neocortex.Recent methodological breakthroughs have enabled longitudinal recordings of defined layer 1 afferent pathways in behaving mice.This work has started to promote a mechanistic understanding of how top-down processing enables cognitive capacities including memory, attention, and predictive coding.Top-down projections from diverse sources including cortical areas, higher-order thalamus, neuromodulatory nuclei, and other subcortical brain regions tune the computations of neocortex via layer 1 in these paradigms.Emerging data suggest that heterosynaptic interactions within layer 1 may further amplify the computational flexibility of top-down processing.
Learning is mediated by experience-dependent plasticity in neuronal circuits. Activity in neuronal circuits is tightly regulated by different subtypes of inhibitory interneurons, yet their role in ...learning is poorly understood. Using a combination of in vivo single-unit recordings and optogenetic manipulations, we show that in the mouse basolateral amygdala, interneurons expressing parvalbumin (PV) and somatostatin (SOM) bidirectionally control the acquisition of fear conditioning--a simple form of associative learning--through two distinct disinhibitory mechanisms. During an auditory cue, PV(+) interneurons are excited and indirectly disinhibit the dendrites of basolateral amygdala principal neurons via SOM(+) interneurons, thereby enhancing auditory responses and promoting cue-shock associations. During an aversive footshock, however, both PV(+) and SOM(+) interneurons are inhibited, which boosts postsynaptic footshock responses and gates learning. These results demonstrate that associative learning is dynamically regulated by the stimulus-specific activation of distinct disinhibitory microcircuits through precise interactions between different subtypes of local interneurons.
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