Journal: Frontiers in neural circuits
The auditory pathways coursing through the brainstem are organized bilaterally in mirror image about the midline and at several levels the two sides are interconnected. One of the most prominent points of interconnection is the commissure of the inferior colliculus (CoIC). Anatomical studies have revealed that these fibers make reciprocal connections which follow the tonotopic organization of the inferior colliculus (IC), and that the commissure contains both excitatory and, albeit fewer, inhibitory fibers. The role of these connections in sound processing is largely unknown. Here we describe a method to address this question in the anaesthetized guinea pig. We used a cryoloop placed on one IC to produce reversible deactivation while recording electrophysiological responses to sounds in both ICs. We recorded single units, multi-unit clusters and local field potentials (LFPs) before, during and after cooling. The degree and spread of cooling was measured with a thermocouple placed in the IC and other auditory structures. Cooling sufficient to eliminate firing was restricted to the IC contacted by the cryoloop. The temperature of other auditory brainstem structures, including the contralateral IC and the cochlea were minimally affected. Cooling below 20°C reduced or eliminated the firing of action potentials in frequency laminae at depths corresponding to characteristic frequencies up to ~8 kHz. Modulation of neural activity also occurred in the un-cooled IC with changes in single unit firing and LFPs. Components of LFPs signaling lemniscal afferent input to the IC showed little change in amplitude or latency with cooling, whereas the later components, which likely reflect inter- and intra-collicular processing, showed marked changes in form and amplitude. We conclude that the cryoloop is an effective method of selectively deactivating one IC in guinea pig, and demonstrate that auditory processing in the IC is strongly influenced by the other.
Juxtaglomerular neurons represent one of the largest cellular populations in the mammalian olfactory bulb yet their role for signal processing remains unclear. We used two-photon imaging and electrophysiological recordings to clarify the properties of these cells and their functional organization in the juxtaglomerular space. Juxtaglomerular neurons coded for many perceptual characteristics of the olfactory stimulus such as (1) identity of the odorant, (2) odorant concentration, (3) odorant onset, and (4) offset. The odor-responsive neurons clustered within a narrow area surrounding the glomerulus with the same odorant specificity, with ~80% of responding cells located ≤20 μm from the glomerular border. This stereotypic spatial pattern of activated cells persisted at different odorant concentrations and was found for neurons both activated and inhibited by the odorant. Our data identify a principal glomerulus with a narrow shell of juxtaglomerular neurons as a basic odor coding unit in the glomerular layer and underline the important role of intraglomerular circuitry.
Auditory neurons that exhibit stimulus-specific adaptation (SSA) decrease their response to common tones while retaining responsiveness to rare ones. We recorded single-unit responses from the inferior colliculus (IC) where SSA is known to occur and we explored for the first time SSA in the cochlear nucleus (CN) of rats. We assessed an important functional outcome of SSA, the extent to which frequency discriminability depends on sensory context. For this purpose, pure tones were presented in an oddball sequence as standard (high probability of occurrence) or deviant (low probability of occurrence) stimuli. To study frequency discriminability under different probability contexts, we varied the probability of occurrence and the frequency separation between tones. The neuronal sensitivity was estimated in terms of spike-count probability using signal detection theory. We reproduced the finding that many neurons in the IC exhibited SSA, but we did not observe significant SSA in our CN sample. We concluded that strong SSA is not a ubiquitous phenomenon in the CN. As predicted, frequency discriminability was enhanced in IC when stimuli were presented in an oddball context, and this enhancement was correlated with the degree of SSA shown by the neurons. In contrast, frequency discrimination by CN neurons was independent of stimulus context. Our results demonstrated that SSA is not widespread along the entire auditory pathway, and suggest that SSA increases frequency discriminability of single neurons beyond that expected from their tuning curves.
Pyramidal neurons represent the majority of excitatory neurons in the neocortex. Each pyramidal neuron receives input from thousands of excitatory synapses that are segregated onto dendritic branches. The dendrites themselves are segregated into apical, basal, and proximal integration zones, which have different properties. It is a mystery how pyramidal neurons integrate the input from thousands of synapses, what role the different dendrites play in this integration, and what kind of network behavior this enables in cortical tissue. It has been previously proposed that non-linear properties of dendrites enable cortical neurons to recognize multiple independent patterns. In this paper we extend this idea in multiple ways. First we show that a neuron with several thousand synapses segregated on active dendrites can recognize hundreds of independent patterns of cellular activity even in the presence of large amounts of noise and pattern variation. We then propose a neuron model where patterns detected on proximal dendrites lead to action potentials, defining the classic receptive field of the neuron, and patterns detected on basal and apical dendrites act as predictions by slightly depolarizing the neuron without generating an action potential. By this mechanism, a neuron can predict its activation in hundreds of independent contexts. We then present a network model based on neurons with these properties that learns time-based sequences. The network relies on fast local inhibition to preferentially activate neurons that are slightly depolarized. Through simulation we show that the network scales well and operates robustly over a wide range of parameters as long as the network uses a sparse distributed code of cellular activations. We contrast the properties of the new network model with several other neural network models to illustrate the relative capabilities of each. We conclude that pyramidal neurons with thousands of synapses, active dendrites, and multiple integration zones create a robust and powerful sequence memory. Given the prevalence and similarity of excitatory neurons throughout the neocortex and the importance of sequence memory in inference and behavior, we propose that this form of sequence memory may be a universal property of neocortical tissue.
Some individuals are resilient, whereas others succumb to despair in repeated stressful situations. The neurobiological mechanisms underlying such divergent behavioral responses remain unclear. Here, we employed an automated method for mapping neuronal activity in search of signatures of stress responses in the entire mouse brain. We used serial two-photon tomography to detect expression of c-FosGFP - a marker of neuronal activation - in c-fosGFP transgenic mice subjected to the learned helplessness (LH) procedure, a widely used model of stress-induced depression-like phenotype in laboratory animals. We found that mice showing “helpless” behavior had an overall brain-wide reduction in the level of neuronal activation compared with mice showing “resilient” behavior, with the exception of a few brain areas, including the locus coeruleus, that were more activated in the helpless mice. In addition, the helpless mice showed a strong trend of having higher similarity in whole-brain activity profile among individuals, suggesting that helplessness is represented by a more stereotypic brain-wide activation pattern. This latter effect was confirmed in rats subjected to the LH procedure, using 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography to assess neural activity. Our findings reveal distinct brain activity markings that correlate with adaptive and maladaptive behavioral responses to stress, and provide a framework for further studies investigating the contribution of specific brain regions to maladaptive stress responses.
Functional loss of limb control in individuals with spinal cord injury or stroke can be caused by interruption of corticospinal pathways, although the neural circuits located above and below the lesion remain functional. An artificial neural connection that bridges the lost pathway and connects cortical to spinal circuits has potential to ameliorate the functional loss. We investigated the effects of introducing novel artificial neural connections in a paretic monkey that had a unilateral spinal cord lesion at the C2 level. The first application bridged the impaired spinal lesion. This allowed the monkey to drive the spinal stimulation through volitionally controlled power of high-gamma activity in either the premotor or motor cortex, and thereby to acquire a force-matching target. The second application created an artificial recurrent connection from a paretic agonist muscle to a spinal site, allowing muscle-controlled spinal stimulation to boost on-going activity in the muscle. These results suggest that artificial neural connections can compensate for interrupted descending pathways and promote volitional control of upper limb movement after damage of descending pathways such as spinal cord injury or stroke.
Ca(2+)/CaM serine/threonine kinase II (CaMKII) is a central molecule in mechanisms of synaptic plasticity and memory. A vital feature of CaMKII in plasticity is its ability to switch to a calcium (Ca(2+)) independent constitutively active state after autophosphorylation at threonine 287 (T287). A second pair of sites, T306 T307 in the calmodulin (CaM) binding region once autophosphorylated, prevent subsequent CaM binding and inactivates the kinase during synaptic plasticity and memory. Recently a synaptic molecule called Ca(2+)/CaM-dependent serine protein kinase (CASK) has been shown to control both sets of CaMKII autophosphorylation events and hence is well poised to be a key regulator of memory. We show deletion of full length CASK or just its CaMK-like and L27 domains disrupts middle-term memory (MTM) and long-term memory (LTM), with CASK function in the α'/β' subset of mushroom body neurons being required for memory. Likewise directly changing the levels of CaMKII autophosphorylation in these neurons removed MTM and LTM. The requirement of CASK and CaMKII autophosphorylation was not developmental as their manipulation just in the adult α'/β' neurons was sufficient to remove memory. Overexpression of CASK or CaMKII in the α'/β' neurons also occluded MTM and LTM. Overexpression of either Drosophila or human CASK in the α'/β' neurons of the CASK mutant completely rescued memory, confirming that CASK signaling in α'/β' neurons is necessary and sufficient for Drosophila memory formation and that the neuronal function of CASK is conserved between Drosophila and human. At the cellular level CaMKII overexpression in the α'/β' neurons increased activity dependent Ca(2+) responses while reduction of CaMKII decreased it. Likewise reducing CASK or directly expressing a phosphomimetic CaMKII T287D transgene in the α'/β' similarly decreased Ca(2+) signaling. Our results are consistent with CASK regulating CaMKII autophosphorylation in a pathway required for memory formation that involves activity dependent changes in Ca(2+) signaling in the α'/β' neurons.
Prey capture behavior critically depends on rapid processing of sensory input in order to track, approach, and catch the target. When using vision, the nervous system faces the problem of extracting relevant information from a continuous stream of input in order to detect and categorize visible objects as potential prey and to select appropriate motor patterns for approach. For prey capture, many vertebrates exhibit intermittent locomotion, in which discrete motor patterns are chained into a sequence, interrupted by short periods of rest. Here, using high-speed recordings of full-length prey capture sequences performed by freely swimming zebrafish larvae in the presence of a single paramecium, we provide a detailed kinematic analysis of first and subsequent swim bouts during prey capture. Using Fourier analysis, we show that individual swim bouts represent an elementary motor pattern. Changes in orientation are directed toward the target on a graded scale and are implemented by an asymmetric tail bend component superimposed on this basic motor pattern. To further investigate the role of visual feedback on the efficiency and speed of this complex behavior, we developed a closed-loop virtual reality setup in which minimally restrained larvae recapitulated interconnected swim patterns closely resembling those observed during prey capture in freely moving fish. Systematic variation of stimulus properties showed that prey capture is initiated within a narrow range of stimulus size and velocity. Furthermore, variations in the delay and location of swim triggered visual feedback showed that the reaction time of secondary and later swims is shorter for stimuli that appear within a narrow spatio-temporal window following a swim. This suggests that the larva may generate an expectation of stimulus position, which enables accelerated motor sequencing if the expectation is met by appropriate visual feedback.
Long-term expression of optogenetic proteins including channelrhodopsin-2 (ChR2) is widely used to study neural circuit function, but whether ChR2 expression itself perturbs circuits is not known. We expressed a common construct, CAG::ChR2 (H134R)-EYFP-WPRE, in L2/3 pyramidal cells in rat somatosensory cortex via in utero DNA electroporation (IUE). L2/3 pyramidal cells expressed ChR2-EYFP, but histology revealed abnormal morphology and targeting of ChR2-EYFP expressing axons, beginning at postnatal day (P) 33 and increasing with age. Axonal abnormalities included cylinders that enveloped pyramidal cell proximal apical dendrites, and spherical, calyx-like structures that surrounded neuronal cell bodies, including in L4. These are abnormal subcellular and laminar targets for L2/3 pyramidal cell synapses. Abnormalities did not occur in cells expressing GFP instead of ChR2, or in intermixed ChR2-negative axons. Long-term viral-mediated expression (80 d) did not cause axonal abnormalities when the CAG promoter was used, but produced some abnormalities with the stronger αCaMKII promoter (albeit much less than with in utero electroporation). Thus, under some circumstances high-level, long-term expression of ChR2-EYFP can perturb the structural organization of cortical circuits.
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder and one of the most common causes of mental retardation in affected girls. Other symptoms include a rapid regression of motor and cognitive skills after an apparently early normal development. Sporadic mutations in the transcription factor MECP2 has been shown to be present in more than 90% of the patients and several models of MeCP2-deficient mice have been created to understand the role of this gene. These models have pointed toward alterations in the maintenance of the central nervous system rather than its development, in line with the late onset of the disease in humans. However, the exact functions of MeCP2 remain difficult to delineate and the animal models have yielded contradictory results. Here, we present the first mecp2-null allele mutation zebrafish model. Surprisingly and in contrast to MeCP2-null mouse models, mecp2-null zebrafish are viable and fertile. They present nonetheless clear behavioral alterations during their early development, including spontaneous and sensory-evoked motor anomalies, as well as defective thigmotaxis.