Neuronal Firing Rate Homeostasis Is Inhibited by Sleep and Promoted by Wake.

Homeostatic mechanisms stabilize neural circuit function by keeping firing rates within a set-point range, but whether this process is gated by brain state is unknown. Here, we monitored firing rate homeostasis in individual visual cortical neurons in freely behaving rats as they cycled between sleep and wake states. When neuronal firing rates were perturbed by visual deprivation, they gradually returned to a precise, cell-autonomous set point during periods of active wake, with lengthening of the wake period enhancing firing rate rebound. Unexpectedly, this resetting of neuronal firing was suppressed during sleep. This raises the possibility that memory consolidation or other sleep-dependent processes are vulnerable to interference from homeostatic plasticity mechanisms. PAPERCLIP.

Impact of Acute Visual Experience on Development of LGN Receptive Fields in the Ferret.

Selectivity for direction of motion is a key feature of primary visual cortical neurons. Visual experience is required for direction selectivity in carnivore and primate visual cortex, but the circuit mechanisms of its formation remain incompletely understood. Here, we examined how developing lateral geniculate nucleus (LGN) neurons may contribute to cortical direction selectivity. Using in vivo electrophysiology techniques, we examined LGN receptive field properties of visually naive female ferrets before and after exposure to 6 h of motion stimuli to assess the effect of acute visual experience on LGN cell development. We found that acute experience with motion stimuli did not significantly affect the weak orientation or direction selectivity of LGN neurons. In addition, we found that neither latency nor sustainedness or transience of LGN neurons significantly changed with acute experience. These results suggest that the direction selectivity that emerges in cortex after acute experience is computed in cortex and cannot be explained by changes in LGN cells.SIGNIFICANCE STATEMENT The development of typical neural circuitry requires experience-independent and experience-dependent factors. In the visual cortex of carnivores and primates, selectivity for motion arises as a result of experience, but we do not understand whether the major brain area that sits between the retina and the visual cortex-the lateral geniculate nucleus of the thalamus-also participates. Here, we found that lateral geniculate neurons do not exhibit changes as a result of several hours of visual experience with moving stimuli at a time when visual cortical neurons undergo a rapid change. We conclude that lateral geniculate neurons do not participate in this plasticity and that changes in cortex are likely responsible for the development of direction selectivity in carnivores and primates.

Experience-Dependent Development of Dendritic Arbors in Mouse Visual Cortex.

The dendritic arbor of neurons constrains the pool of available synaptic partners and influences the electrical integration of synaptic currents. Despite these critical functions, our knowledge of the dendritic structure of cortical neurons during early postnatal development and how these dendritic structures are modified by visual experience is incomplete. Here, we present a large-scale dataset of 849 3D reconstructions of the basal arbor of pyramidal neurons collected across early postnatal development in visual cortex of mice of either sex. We found that the basal arbor grew substantially between postnatal day 7 (P7) and P30, undergoing a 45% increase in total length. However, the gross number of primary neurites and dendritic segments was largely determined by P7. Growth from P7 to P30 occurred primarily through extension of dendritic segments. Surprisingly, comparisons of dark-reared and typically reared mice revealed that a net gain of only 15% arbor length could be attributed to visual experience; most growth was independent of experience. To examine molecular contributions, we characterized the role of the activity-regulated small GTPase Rem2 in both arbor development and the maintenance of established basal arbors. We showed that Rem2 is an experience-dependent negative regulator of dendritic segment number during the visual critical period. Acute deletion of Rem2 reduced directionality of dendritic arbors. The data presented here establish a highly detailed, quantitative analysis of basal arbor development that we believe has high utility both in understanding circuit development as well as providing a framework for computationalists wishing to generate anatomically accurate neuronal models.SIGNIFICANCE STATEMENT Dendrites are the sites of the synaptic connections among neurons. Despite their importance for neural circuit function, only a little is known about the postnatal development of dendritic arbors of cortical pyramidal neurons and the influence of experience. Here we show that the number of primary basal dendritic arbors is already established before eye opening, and that these arbors primarily grow through lengthening of dendritic segments and not through addition of dendritic segments. Surprisingly, visual experience has a modest net impact on overall arbor length (15%). Experiments in KO animals revealed that the gene Rem2 is positive regulator of dendritic length and a negative regulator of dendritic segments.

Development of Cross-Orientation Suppression and Size Tuning and the Role of Experience.

Many sensory neural circuits exhibit response normalization, which occurs when the response of a neuron to a combination of multiple stimuli is less than the sum of the responses to the individual stimuli presented alone. In the visual cortex, normalization takes the forms of cross-orientation suppression and surround suppression. At the onset of visual experience, visual circuits are partially developed and exhibit some mature features such as orientation selectivity, but it is unknown whether cross-orientation suppression is present at the onset of visual experience or requires visual experience for its emergence. We characterized the development of normalization and its dependence on visual experience in female ferrets. Visual experience was varied across the following three conditions: typical rearing, dark rearing, and dark rearing with daily exposure to simple sinusoidal gratings (14-16 h total). Cross-orientation suppression and surround suppression were noted in the earliest observations, and did not vary considerably with experience. We also observed evidence of continued maturation of receptive field properties in the second month of visual experience: substantial length summation was observed only in the oldest animals (postnatal day 90); evoked firing rates were greatly increased in older animals; and direction selectivity required experience, but declined slightly in older animals. These results constrain the space of possible circuit implementations of these features.SIGNIFICANCE STATEMENT The development of the brain depends on both nature-factors that are independent of the experience of an individual animal-and nurture-factors that depend on experience. While orientation selectivity, one of the major response properties of neurons in visual cortex, is already present at the onset of visual experience, it is unknown whether response properties that depend on interactions among multiple stimuli develop without experience. We find that the properties of cross-orientation suppression and surround suppression are present at eye opening, and do not depend on visual experience. Our results are consistent with the idea that a majority of the basic properties of sensory neurons in primary visual cortex are derived independent of the experience of an individual animal.

Visual Stimulus Speed Does Not Influence the Rapid Emergence of Direction Selectivity in Ferret Visual Cortex.

Sensory experience is necessary for the development of some receptive field properties of neurons in primary sensory cortical areas. However, it remains unclear whether the parameters of an individual animal's experience play an instructive role and influence the tuning parameters of cortical sensory neurons as selectivity emerges, or rather whether experience merely permits the completion of processes that are fully seeded at the onset of experience. Here we have examined whether the speed of visual stimuli that are presented to visually naive ferrets can influence the parameters of speed tuning and direction selectivity in cortical neurons. Visual experience is necessary for the development of direction selectivity in carnivores. If, during development, cortical neurons had the flexibility to choose from among different inputs with a range of spatial positions and temporal delays, then correlation-based plasticity mechanisms could instruct the precise spatiotemporal selectivity that underlies speed tuning and direction selectivity, and the parameters of an individual animal's experience would influence the tuning that emerges. Alternatively, the tuning parameters of these neurons may already be established at the onset of visual experience, and experience may merely permit the expression of this tuning. We found that providing different groups of animals with either slow (12.5 deg/s) or fast (50 deg/s) visual stimuli resulted in emergence of direction selectivity, but that speed tuning and direction selectivity were similar in the two groups. These results are more consistent with a permissive role for experience in the development of direction selectivity.SIGNIFICANCE STATEMENT The proper development of brain circuits and neural response properties depends on both nature (factors independent of experience) and nurture (factors dependent on experience). In this study, we examined whether the quality of visual experience of an individual animal influences the development of basic sensory detectors in primary visual cortex. We found that, although visual experience is required for the development of direction selectivity, tuning for stimulus speed could not be altered by specific experience with slow or fast stimuli. These results suggest that the tuning parameters for direction selectivity are specified independently of an animal's sensory experience, and that a range of experiences can promote the proper mature expression of direction selectivity in primary visual cortex.

Neural architecture: from cells to circuits.

Circuit operations are determined jointly by the properties of the circuit elements and the properties of the connections among these elements. In the nervous system, neurons exhibit diverse morphologies and branching patterns, allowing rich compartmentalization within individual cells and complex synaptic interactions among groups of cells. In this review, we summarize work detailing how neuronal morphology impacts neural circuit function. In particular, we consider example neurons in the retina, cerebral cortex, and the stomatogastric ganglion of crustaceans. We also explore molecular coregulators of morphology and circuit function to begin bridging the gap between molecular and systems approaches. By identifying motifs in different systems, we move closer to understanding the structure-function relationships that are present in neural circuits.

Cortical amplification models of experience-dependent development of selective columns and response sparsification.

The development of direction-selective cortical columns requires visual experience, but the neural circuits and plasticity mechanisms that are responsible for this developmental transition are unknown. To gain insight into the mechanisms that could underlie experience-dependent increases in selectivity, we explored families of cortical amplifier models that enhance weakly biased feedforward signals. Here we focused exclusively on possible contributions of cortico-cortical connections and took feedforward input to be constant. We modeled pairs of interconnected columns that received equal and oppositely biased inputs. In a single-element model of cortical columns, we found two ways that cortical columns could receive biased feedforward input and exhibit strong but unselective responses to stimuli: 1) within-column recurrent excitatory connections could be strong enough to amplify both strong and weak feedforward input, or 2) columns that received differently biased inputs could have strong excitatory cross-connections that destroy selectivity. A Hebbian plasticity rule combined with simulated experience with stimuli weakened these strong cross-connections across cortical columns, allowing the individual columns to respond selectively to their biased inputs. In a model that included both excitatory and inhibitory neurons in each column, an additional means of obtaining selectivity through the cortical circuit was uncovered: cross-column suppression of inhibition-stabilized networks. When each column operated as an inhibition-stabilized network, cross-column excitation onto inhibitory neurons forced competition between the columns but in a manner that did not involve strong null-direction inhibition, consistent with experimental measurements of direction selectivity in visual cortex. Experimental predictions of these possible contributions of cortical circuits are discussed.NEW & NOTEWORTHY Sensory circuits are initially constructed via mechanisms that are independent of sensory experience, but later refinement requires experience. We constructed models of how circuits that receive biased feedforward inputs can be initially unselective and then be modified by experience and plasticity so that the resulting circuit exhibits increased selectivity. We propose that neighboring cortical columns may initially exhibit coupling that is too strong for selectivity. Experience-dependent mechanisms decrease this coupling so individual columns can exhibit selectivity.

Optogenetic spatial and temporal control of cortical circuits on a columnar scale.

Many circuits in the mammalian brain are organized in a topographic or columnar manner. These circuits could be activated-in ways that reveal circuit function or restore function after disease-by an artificial stimulation system that is capable of independently driving local groups of neurons. Here we present a simple custom microscope called ProjectorScope 1 that incorporates off-the-shelf parts and a liquid crystal display (LCD) projector to stimulate surface brain regions that express channelrhodopsin-2 (ChR2). In principle, local optogenetic stimulation of the brain surface with optical projection systems might not produce local activation of a highly interconnected network like the cortex, because of potential stimulation of axons of passage or extended dendritic trees. However, here we demonstrate that the combination of virally mediated ChR2 expression levels and the light intensity of ProjectorScope 1 is capable of producing local spatial activation with a resolution of ∼200-300 µm. We use the system to examine the role of cortical activity in the experience-dependent emergence of motion selectivity in immature ferret visual cortex. We find that optogenetic cortical activation alone-without visual stimulation-is sufficient to produce increases in motion selectivity, suggesting the presence of a sharpening mechanism that does not require precise spatiotemporal activation of the visual system. These results demonstrate that optogenetic stimulation can sculpt the developing brain.

Rem2 is an activity-dependent negative regulator of dendritic complexity in vivo.

A key feature of the CNS is structural plasticity, the ability of neurons to alter their morphology and connectivity in response to sensory experience and other changes in the environment. How this structural plasticity is achieved at the molecular level is not well understood. We provide evidence that changes in sensory experience simultaneously trigger multiple signaling pathways that either promote or restrict growth of the dendritic arbor; structural plasticity is achieved through a balance of these opposing signals. Specifically, we have uncovered a novel, activity-dependent signaling pathway that restricts dendritic arborization. We demonstrate that the GTPase Rem2 is regulated at the transcriptional level by calcium influx through L-VGCCs and inhibits dendritic arborization in cultured rat cortical neurons and in the Xenopus laevis tadpole visual system. Thus, our results demonstrate that changes in neuronal activity initiate competing signaling pathways that positively and negatively regulate the growth of the dendritic arbor. It is the balance of these opposing signals that leads to proper dendritic morphology.

Weak orientation and direction selectivity in lateral geniculate nucleus representing central vision in the gray squirrel Sciurus carolinensis.

Classic studies of lateral geniculate nucleus (LGN) and visual cortex (V1) in carnivores and primates have found that a majority of neurons in LGN exhibit a center-surround organization, while V1 neurons exhibit strong orientation selectivity and, in many species, direction selectivity. Recent work in the mouse and the monkey has discovered previously unknown classes of orientation- and direction-selective neurons in LGN. Furthermore, some recent studies in the mouse report that many LGN cells exhibit pronounced orientation biases that are of comparable strength to the subthreshold inputs to V1 neurons. These results raise the possibility that, in rodents, orientation biases of individual LGN cells make a substantial contribution to cortical orientation selectivity. Alternatively, the size and contribution of orientation- or direction-selective channels from LGN to V1 may vary across mammals. To address this question, we examined orientation and direction selectivity in LGN and V1 neurons of a highly visual diurnal rodent: the gray squirrel. In the representation of central vision, only a few LGN neurons exhibited strong orientation or direction selectivity. Across the population, LGN neurons showed weak orientation biases and were much less selective for orientation compared with V1 neurons. Although direction selectivity was weak overall, LGN layers 3abc, which contain neurons that express calbindin, exhibited elevated direction selectivity index values compared with LGN layers 1 and 2. These results suggest that, for central visual fields, the contribution of orientation- and direction-selective channels from the LGN to V1 is small in the squirrel. As in other mammals, this small contribution is elevated in the calbindin-positive layers of the LGN.

Transformation of receptive field properties from lateral geniculate nucleus to superficial V1 in the tree shrew.

Tree shrew primary visual cortex (V1) exhibits a pronounced laminar segregation of inputs from different classes of relay neurons in the lateral geniculate nucleus (LGN). We examined how several receptive field (RF) properties were transformed from LGN to V1 layer 4 to V1 layer 2/3. The progression of RF properties across these stages differed markedly from that found in the cat. V1 layer 4 cells are largely similar to the the LGN cells that provide their input, being dominated by a single sign (ON or OFF) and being strongly modulated by sinusoidal gratings. Some layer 4 neurons, notably those near the edges of layer 4, exhibited increased orientation selectivity, and most layer 4 neurons exhibited a preference for lower temporal frequencies. Neurons in cortical layer 2/3 differ significantly from those in the LGN; most exhibited strong orientation tuning and both ON and OFF responses. The strength of orientation selectivity exhibited a notable sublaminar organization, with the strongest orientation tuned neurons in the most superficial parts of layer 2/3. Modulation indexes provide evidence for simple and complex cells in both layer 4 and layer 2/3. However, neurons with high modulation indexes were heterogenous in the spatial organization of ON and OFF responses, with many of them exhibiting unbalanced ON and OFF responses rather than well-segregated ON and OFF subunits. When compared to the laminar organization of V1 in other mammals, these data show that the process of natural selection can result in significantly altered structure/function relationships in homologous cortical circuits.

Emerging feed-forward inhibition allows the robust formation of direction selectivity in the developing ferret visual cortex.

The computation of direction selectivity requires that a cell respond to joint spatial and temporal characteristics of the stimulus that cannot be separated into independent components. Direction selectivity in ferret visual cortex is not present at the time of eye opening but instead develops in the days and weeks following eye opening in a process that requires visual experience with moving stimuli. Classic Hebbian or spike timing-dependent modification of excitatory feed-forward synaptic inputs is unable to produce direction-selective cells from unselective or weakly directionally biased initial conditions because inputs eventually grow so strong that they can independently drive cortical neurons, violating the joint spatial-temporal activation requirement. Furthermore, without some form of synaptic competition, cells cannot develop direction selectivity in response to training with bidirectional stimulation, as cells in ferret visual cortex do. We show that imposing a maximum lateral geniculate nucleus (LGN)-to-cortex synaptic weight allows neurons to develop direction-selective responses that maintain the requirement for joint spatial and temporal activation. We demonstrate that a novel form of inhibitory plasticity, postsynaptic activity-dependent long-term potentiation of inhibition (POSD-LTPi), which operates in the developing cortex at the time of eye opening, can provide synaptic competition and enables robust development of direction-selective receptive fields with unidirectional or bidirectional stimulation. We propose a general model of the development of spatiotemporal receptive fields that consists of two phases: an experience-independent establishment of initial biases, followed by an experience-dependent amplification or modification of these biases via correlation-based plasticity of excitatory inputs that compete against gradually increasing feed-forward inhibition.

Experience with moving visual stimuli drives the early development of cortical direction selectivity.

The onset of vision occurs when neural circuits in the visual cortex are immature, lacking both the full complement of connections and the response selectivity that defines functional maturity. Direction-selective responses are particularly vulnerable to the effects of early visual deprivation, but it remains unclear how stimulus-driven neural activity guides the emergence of cortical direction selectivity. Here we report observations from a motion training protocol that allowed us to monitor the impact of experience on the development of direction-selective responses in visually naive ferrets. Using intrinsic signal imaging techniques, we found that training with a single axis of motion induced the rapid emergence of direction columns that were confined to cortical regions preferentially activated by the training stimulus. Using two-photon calcium imaging techniques, we found that single neurons in visually naive animals exhibited weak directional biases and lacked the strong local coherence in the spatial organization of direction preference that was evident in mature animals. Training with a moving stimulus, but not with a flashed stimulus, strengthened the direction-selective responses of individual neurons and preferentially reversed the direction biases of neurons that deviated from their neighbours. Both effects contributed to an increase in local coherence. We conclude that early experience with moving visual stimuli drives the rapid emergence of direction-selective responses in the visual cortex.

Progressive Circuit Hyperexcitability in Mouse Neocortical Slice Cultures with Increasing Duration of Activity Silencing.

Forebrain neurons deprived of activity become hyperactive when activity is restored. Rebound activity has been linked to spontaneous seizures in vivo following prolonged activity blockade. Here, we measured the time course of rebound activity and the contributing circuit mechanisms using calcium imaging, synaptic staining, and whole-cell patch clamp in organotypic slice cultures of mouse neocortex. Calcium imaging revealed hypersynchronous activity increasing in intensity with longer periods of deprivation. While activity partially recovered 3 d after slices were released from 5 d of deprivation, they were less able to recover after 10 d of deprivation. However, even after the longer period of deprivation, activity patterns eventually returned to baseline levels. The degree of deprivation-induced rebound was age-dependent, with the greatest effects occurring when silencing began in the second week. Pharmacological blockade of NMDA receptors indicated that hypersynchronous rebound activity did not require activation of Hebbian plasticity. In single-neuron recordings, input resistance roughly doubled with a concomitant increase in intrinsic excitability. Synaptic imaging of pre- and postsynaptic proteins revealed dramatic reductions in the number of presumptive synapses with a larger effect on inhibitory than excitatory synapses. Putative excitatory synapses colocalizing PSD-95 and Bassoon declined by 39 and 56% following 5 and 10 d of deprivation, but presumptive inhibitory synapses colocalizing gephyrin and VGAT declined by 55 and 73%, respectively. The results suggest that with prolonged deprivation, a progressive reduction in synapse number is accompanied by a shift in the balance between excitation and inhibition and increased cellular excitability.

Prolonged Activity Deprivation Causes Pre- and Postsynaptic Compensatory Plasticity at Neocortical Excitatory Synapses.

Homeostatic plasticity stabilizes firing rates of neurons, but the pressure to restore low activity rates can significantly alter synaptic and cellular properties. Most previous studies of homeostatic readjustment to complete activity silencing in rodent forebrain have examined changes after 2 d of deprivation, but it is known that longer periods of deprivation can produce adverse effects. To better understand the mechanisms underlying these effects and to address how presynaptic as well as postsynaptic compartments change during homeostatic plasticity, we subjected mouse cortical slice cultures to a more severe 5 d deprivation paradigm. We developed and validated a computational framework to measure the number and morphology of presynaptic and postsynaptic compartments from super-resolution light microscopy images of dense cortical tissue. Using these tools, combined with electrophysiological miniature excitatory postsynaptic current measurements, and synaptic imaging at the electron microscopy level, we assessed the functional and morphological results of prolonged deprivation. Excitatory synapses were strengthened both presynaptically and postsynaptically. Surprisingly, we also observed a decrement in the density of excitatory synapses, both as measured from colocalized staining of pre- and postsynaptic proteins in tissue and from the number of dendritic spines. Overall, our results suggest that cortical networks deprived of activity progressively move toward a smaller population of stronger synapses.

The laminar development of direction selectivity in ferret visual cortex.

Sensory experience plays a critical role in the development of cortical circuits. At the time of eye opening, visual cortical neurons in the ferret exhibit orientation selectivity, but lack direction selectivity, which is a feature of mature cortical neurons in this species. Direction selectivity emerges in the days and weeks following eye opening via a process that requires visual experience. However, the circuit mechanisms that underlie the development of direction selectivity remain unclear. Here, we used microelectrodes to examine the laminar chronology of the development of direction selectivity around the time of eye opening to identify the locations within the cortical circuit that are altered during this process. We found that neurons in layers 4 and 2/3 exhibited weak direction selectivity just before natural eye opening. Layer 4 neurons in animals that had opened their eyes but were younger than postnatal day 35 (PND 35) exhibited modestly increased direction selectivity, but layer 2/3 cells remained as weakly tuned as before eye opening. Animals that had opened their eyes and were PND 35 or older exhibited increased direction selectivity in both layers 4 and 2/3. On average, initial increases in direction selectivity in animals younger than PND 35 were explained by increases in responses to the preferred direction, while subsequent increases in direction selectivity in animals PND 35 or older were explained by decreases in responses to the null direction. These results suggest that all cortical layers are influenced by sensory stimulation during early stages of experience-dependent development.

Initial neighborhood biases and the quality of motion stimulation jointly influence the rapid emergence of direction preference in visual cortex.

Visual experience plays a critical role in the development of direction-selective responses in ferret visual cortex. In visually naive animals, presentation of a bidirectional "training" stimulus induces rapid increases in the direction-selective responses of single neurons that can be predicted by small but significant direction biases that are present in neighboring neurons at the onset of stimulation. In this study we used in vivo two-photon imaging of calcium signals to further explore the contribution of visual experience to the emergence of direction- selective responses in ferret visual cortex. The first set of experiments was designed to determine whether visual experience is required for the development of the initial neighborhood bias. In animals that were dark-reared until the time of eye opening, we found that individual neurons exhibited weak direction-selective responses accompanied by a reduced but statistically significant neighborhood bias, indicating that both features arise without the need for visual experience. The second set of experiments used a unidirectional training stimulus to assess the relative roles of the neighborhood bias and visual experience in determining the direction preference that cortical neurons acquire during direction training. We found that neurons became more responsive to the trained direction even when they were located in regions of the cortex with an initial neighborhood bias for the direction opposite the training stimulus. Together, these results suggest an adaptive developmental strategy for the elaboration of direction-selective responses, one in which experience-independent mechanisms provide a symmetry-breaking seed for the instructive effects of visual experience.

A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex.

Healthy neuronal networks rely on homeostatic plasticity to maintain stable firing rates despite changing synaptic drive. These mechanisms, however, can themselves be destabilizing if activated inappropriately or excessively. For example, prolonged activity deprivation can lead to rebound hyperactivity and seizures. While many forms of homeostasis have been described, whether and how the magnitude of homeostatic plasticity is constrained remains unknown. Here, we uncover negative regulation of cortical network homeostasis by the PARbZIP family of transcription factors. In cortical slice cultures made from knockout mice lacking all three of these factors, the network response to prolonged activity withdrawal measured with calcium imaging is much stronger, while baseline activity is unchanged. Whole-cell recordings reveal an exaggerated increase in the frequency of miniature excitatory synaptic currents reflecting enhanced upregulation of recurrent excitatory synaptic transmission. Genetic analyses reveal that two of the factors, Hlf and Tef, are critical for constraining plasticity and for preventing life-threatening seizures. These data indicate that transcriptional activation is not only required for many forms of homeostatic plasticity but is also involved in restraint of the response to activity deprivation.

The human brain is made up of billions of nerve cells called neurons which receive and send signals to one another. To avoid being over- or under-stimulated, neurons can adjust the strength of the inputs they receive by altering how connected they are to other nerve cells. This process, known as homeostatic plasticity, is thought to be necessary for normal brain activity as it helps keep the outgoing signals of neurons relatively constant. However, homeostatic plasticity can lead to seizures if it becomes too strong and overcompensates for weak input signals. Regulating this process is therefore central to brain health, but scientists do not understand if or how it is controlled. To address this, Valakh et al. analyzed the genes activated in neurons lacking incoming signals to find proteins that regulate homeostatic plasticity. This revealed a class of molecules called transcription factors (which switch genes on or off) that constrain the process. In brain samples from mice without these regulatory proteins, neurons received twice as much input, leading to an increase in brain activity resembling that observed during seizures. Valakh et al. confirmed this finding using live mice, which developed seizures in the absence of these transcription factors. These findings suggest that this type of regulation to keep homeostatic plasticity from becoming too strong may be important. This could be especially vital as the brain develops, when the strength of connections between neurons changes rapidly. The discovery of the transcription factors involved provides a potential target for activating or restraining homeostatic plasticity. This control could help researchers better understand how the process stabilizes brain signaling.

Development of Functional Properties in the Early Visual System: New Appreciations of the Roles of Lateral Geniculate Nucleus.

In the years following Hubel and Wiesel's first reports on ocular dominance plasticity and amblyopia, much attention has been focused on understanding the role of cortical circuits in developmental and experience-dependent plasticity. Initial studies found few differences between retinal ganglion cells and neurons in the lateral geniculate nucleus and uncovered little evidence for an impact of altered visual experience on the functional properties of lateral geniculate nucleus neurons. In the last two decades, however, studies have revealed that the connectivity between the retina and lateral geniculate nucleus is much richer than was previously appreciated, even revealing visual plasticity - including ocular dominance plasticity - in lateral geniculate nucleus neurons. Here we review the development of the early visual system and the impact of experience with a distinct focus on recent discoveries about lateral geniculate nucleus, its connectivity, and evidence for its plasticity and rigidity during development.

Juvenile Shank3 KO Mice Adopt Distinct Hunting Strategies during Prey Capture Learning.

Mice are opportunistic omnivores that readily learn to hunt and eat insects such as crickets. The details of how mice learn these behaviors and how these behaviors may differ in strains with altered neuroplasticity are unclear. We quantified the behavior of juvenile wild-type (WT) and Shank3 knock-out (KO) mice as they learned to hunt crickets during the critical period for ocular dominance plasticity. This stage involves heightened cortical plasticity including homeostatic synaptic scaling, which requires Shank3, a glutamatergic synaptic protein that, when mutated, produces Phelan-McDermid syndrome and is often comorbid with autism spectrum disorder (ASD). Both strains showed interest in examining live and dead crickets and learned to hunt. Shank3 knock-out mice took longer to become proficient, and, after 5 d, did not achieve the efficiency of wild-type mice in either time-to-capture or distance-to-capture. Shank3 knock-out mice also exhibited different characteristics when pursuing crickets that could not be explained by a simple motor deficit. Although both genotypes moved at the same average speed when approaching a cricket, Shank3 KO mice paused more often, did not begin final accelerations toward crickets as early, and did not close the distance gap to the cricket as quickly as wild-type mice. These differences in Shank3 KO mice are reminiscent of some behavioral characteristics of individuals with ASD as they perform complex tasks, such as slower action initiation and completion. This paradigm will be useful for exploring the neural circuit mechanisms that underlie these learning and performance differences in monogenic ASD rodent models.