Tansu Celikel

Modulation of spike timing by sensory deprivation during induction of cortical map plasticity

Deprivation-induced plasticity of sensory cortical maps involves long-term potentiation (LTP) and depression (LTD) of cortical synapses, but how sensory deprivation triggers LTP and LTD in vivo is unknown. Here we tested whether spike timing–dependent forms of LTP and LTD are involved in this process. We measured spike trains from neurons in layer 4 (L4) and layers 2 and 3 (L2/3) of rat somatosensory cortex before and after acute whisker deprivation, a manipulation that induces whisker map plasticity involving LTD at L4-to-L2/3 (L4–L2/3) synapses. Whisker deprivation caused an immediate reversal of firing order for most L4 and L2/3 neurons and a substantial decorrelation of spike trains, changes known to drive timing-dependent LTD at L4–L2/3 synapses in vitro. In contrast, spike rate changed only modestly. Thus, whisker deprivation is likely to drive map plasticity by spike timing–dependent mechanisms.

Mice lacking the AMPA GluR1 receptor exhibit striatal hyperdopaminergia and 'schizophrenia-related' behaviors.

There is growing evidence implicating dysfunctional glutamatergic neurotransmission and abnormal interactions between the glutamate and dopamine (DA) systems in the pathophysiology of various neuropsychiatric disorders including schizophrenia. The present study evaluated knockout (KO) mice lacking the L-α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) GluR1 receptor subunit for a range of behaviors considered relevant to certain symptoms of schizophrenia. KO showed locomotor hyperactivity during exposure to open field and in response to a novel object, but normal activity in a familiar home cage. Open field locomotor hyperactivity in KO was effectively normalized to WT levels by treatment with the DA antagonist and neuroleptic haloperidol, while locomotor stimulant effects of the NMDA receptor antagonist MK-801 were absent in KO. Social behaviors during a dyadic conspecific encounter were disorganized in KO. KO showed deficits in prepulse inhibition of the acoustic startle response. In vivo chronoamperometric measurement of extracellular DA clearance in striatum demonstrated retarded clearance in KO. These data demonstrate behavioral abnormalities potentially pertinent to schizophrenia in GluR1 KO, together with evidence of dysregulated DA function. Present findings provide novel insight into the potential role of GluR1, AMPA receptors and glutamate × DA interactions in the pathophysiology of schizophrenia and other neuropsychiatric conditions.

Ongoing in Vivo Experience Triggers Synaptic Metaplasticity in the Neocortex

In vivo experience can occlude subsequent induction of long-term potentiation and enhance long-term depression of synaptic responses. Although a reduced capacity for synaptic strengthening may function to prevent excessive excitation, such an effect paradoxically implies that continued experience or training should not improve and may even degrade neural representations. In mice, we examined the effect of ongoing whisker stimulation on synaptic strengthening at layer 4-2/3 synapses in the barrel cortex. Although N-methyl-d-aspartate receptors were required to initiate strengthening, they subsequently suppressed further potentiation at these synapses in vitro and in vivo. Despite this transition, synaptic strengthening continued with additional sensory activity but instead required the activation of metabotropic glutamate receptors, suggesting a mechanism by which continued experience can result in increasing synaptic strength over time.

Unsupervised Whisker Tracking in Unrestrained Behaving Animals

Understanding how whisker-based tactile information is represented in the nervous system requires quantification of sensory input and observation of neural activity during whisking and whisker touch. Chronic electrophysiological methods have long been available to study neural responses in awake and behaving animals; however, methods to quantify the sensory input on whiskers have not yet been developed. Here we describe an unsupervised algorithm to track whisker movements in high-speed video recordings and to quantify the statistics of the tactile information on whiskers in freely behaving animals during haptic object exploration. The algorithm does not require human identification of whiskers, nor does it assume the shape, location, orientation, length of whiskers, or direction of the whisker movements. The algorithm performs well on temporary loss of whisker visibility and under low-light/low-contrast conditions even with inherent anisotropic noise and non-Gaussian variability in the signal. Using this algorithm, we define the speed [protraction (P), 1,081 +/- 322; retraction (R), 1,564 +/- 549 degrees /s], duration (P, 34 +/- 10; R, 24 +/- 8 ms), amplitude (P = R, 40 +/- 13 degrees ), and frequency (19 +/- 7 Hz) of active whisking in freely behaving mice. We furthermore quantify whisker deflection induced changes in whisking kinematics and calculate the statistics (i.e., speed, amplitude and duration) of whisker touch and finally show that whisker deprivation does not alter whisking kinematics during haptic exploration.

Sensory integration across space and in time for decision making in the somatosensory system of rodents

Environment is represented in the brain by a neural code that is a result of the spatiotemporal pattern of incoming sensory information. Sensory neurons encode inputs across space and in time such that activity of a given cell inhibits the ability of near-simultaneously arriving sensory stimuli to excite the cell. At the behavioral level, consequences of such suppression are unknown. We investigated the contribution of spatially distributed, near-simultaneous sensory inputs to decision making in a whisker-dependent learning task. Mice learned the task with a single whisker or multiple whiskers alike. Both groups of mice had similar learning curves and final success rates. However, multiple-whisker animals had faster response times than single-whisker mice, requiring only about half the time to perform the task successfully. The results show that spatially distributed sensory inputs in a highly redundant sensory environment improve speed but not accuracy of the decisions made during simple sensory detection. Suppression of the near-simultaneous sensory inputs could, therefore, act to reduce the sensory redundancy.

Forebrain-Specific Glutamate Receptor B Deletion Impairs Spatial Memory But Not Hippocampal Field Long-Term Potentiation

We demonstrate the fundamental importance of glutamate receptor B (GluR-B) containing AMPA receptors in hippocampal function by analyzing mice with conditional GluR-B deficiency in postnatal forebrain principal neurons (GluR-BΔFb). These mice are as adults sufficiently robust to permit comparative cellular, physiological, and behavioral studies. GluR-B loss induced moderate long-term changes in the hippocampus of GluR-BΔFb mice. Parvalbumin-expressing interneurons in the dentate gyrus and the pyramidal cells in CA3 were decreased in number, and neurogenesis in the subgranular zone was diminished. Excitatory synaptic CA3-to-CA1 transmission was reduced, although synaptic excitability, as quantified by the lowered threshold for population spike initiation, was increased compared with control mice. These changes did not alter CA3-to-CA1 long-term potentiation (LTP), which in magnitude was similar to LTP in control mice. The altered hippocampal circuitry, however, affected spatial learning in GluR-BΔFb mice. The primary source for the observed changes is most likely the AMPA receptor-mediated Ca2+ signaling that appears after GluR-B depletion, because we observed similar alterations in GluR-BQFb mice in which the expression of Ca2+-permeable AMPA receptors in principal neurons was induced by postnatal activation of a Q/R-site editing-deficient GluR-B allele.

Select Overexpression of Homer1a in Dorsal Hippocampus Impairs Spatial Working Memory

Long Homer proteins forge assemblies of signaling components involved in glutamate receptor signaling in postsynaptic excitatory neurons, including those underlying synaptic transmission and plasticity. The short immediate-early gene (IEG) Homer1a can dynamically uncouple these physical associations by functional competition with long Homer isoforms. To examine the consequences of Homer1a-mediated “uncoupling” for synaptic plasticity and behavior, we generated forebrain-specific tetracycline (tet) controlled expression of Venus-tagged Homer1a (H1aV) in mice. We report that sustained overexpression of H1aV impaired spatial working but not reference memory. Most notably, a similar impairment was observed when H1aV expression was restricted to the dorsal hippocampus (HP), which identifies this structure as the principal cortical area for spatial working memory. Interestingly, H1aV overexpression also abolished maintenance of CA3-CA1 long-term potentiation (LTP). These impairments, generated by sustained high Homer1a levels, identify a requirement for long Homer forms in synaptic plasticity and temporal encoding of spatial memory.

The role of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in depression: Central mediators of pathophysiology and antidepressant activity?

Depression is a major psychiatric disorder affecting more than 120 million people worldwide every year. Changes in monoaminergic transmitter release are suggested to take part in the pathophysiology of depression. However, more recent experimental evidence suggests that glutamatergic mechanisms might play a more central role in the development of this disorder. The importance of the glutamatergic system in depression was particularly highlighted by the discovery that N-methyl-D-aspartate (NMDA) receptor antagonists (particularly ketamine) exert relatively long-lasting antidepressant like effects with rapid onset. Importantly, the antidepressant-like effects of NMDA receptor antagonists, but also other antidepressants (both classical and novel), require activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Additionally, expression of AMPA receptors is altered in patients with depression. Moreover, preclinical evidence supports an important involvement of AMPA receptor-dependent signaling and plasticity in the pathophysiology and treatment of depression. Here we summarize work published on the involvement of AMPA receptors in depression and discuss a possible central role for AMPA receptors in the pathophysiology, course and treatment of depression.

Tactile object localization by anticipatory whisker motion

Rodents use rhythmic protractions of their whiskers to locate objects in space. The amplitude of these protractions is reduced when whiskers contact objects, leading to a tendency of whiskers to only lightly touch the environment. While the impact of this process on the sensory input has been studied, little is known about how sensory input causes this change in the motor pattern. Here, using high-speed imaging of whisking in mice, we simultaneously measured whisker contacts and the resulting whisking motion. We found that mice precisely target their whisker protractions to the distance at which they expect objects. This modulation does not depend on the current sensory input and remains stable for at least one whisking cycle when there is no object contact or when the object position is changed. As a result, the timing and other information carried by whisker contacts encodes how well each protraction was matched to the object, functioning as an error signal. Whisker contacts can thus encode a mismatch between expected object locations and the actual environment.

Determinants of the mouse ultrasonic vocal structure and repertoire

Mouse ultrasonic vocalizations (USV) exhibit a high degree of complexity as demonstrated in recent years. A multitude of factors have been identified to influence USVs on the spectrotemporal as well as structural - e.g. syntactic - level. A synthesis of the various studies that attributes semantics to USV properties or sequences is still lacking. Presently, we address the factors modulating the composition of USVs, specifically age, gender, genetic background (including the targeted FoxP2 mutagenesis), behavioral state and individuality. It emerges that the different factors share a set of common influences, e.g. vocalization rate and frequency range are universally modulated across independent variables described; however, distinct influences exist for sequential structure (different effects for age, behavioral state and genetic background) or vocal repertoire (age). Recently, USV research has seen important advances based on the quantitative maturation of methods on multiple levels of vocalization. Adoption of these methods to address the natural statistics of USV will ultimately benefit several related research areas, e.g. neurolinguistics, neurodevelopmental disorders, multisensory and sensorimotor research.