Carl R. Stoelzel

Stability of Thalamocortical Synaptic Transmission across Awake Brain States

Sensory cortical neurons are highly sensitive to brain state, with many neurons showing changes in spatial and/or temporal response properties and some neurons becoming virtually unresponsive when subjects are not alert. Although some of these changes are undoubtedly attributable to state-related filtering at the thalamic level, another likely source of such effects is the thalamocortical (TC) synapse, where activation of nicotinic receptors on TC terminals have been shown to enhance synaptic transmission in vitro. However, monosynaptic TC synaptic transmission has not been directly examined during different states of alertness. Here, in awake rabbits that shifted between alert and non-alert EEG states, we examined the monosynaptic TC responses and short-term synaptic dynamics generated by spontaneous impulses of single visual and somatosensory TC neurons. We did this using spike-triggered current source-density analysis, an approach that enables assessment of monosynaptic extracellular currents generated in different cortical layers by impulses of single TC afferents. Spontaneous firing rates of TC neurons were higher, and burst rates were much lower in the alert state. However, we found no state-related changes in the amplitude of monosynaptic TC responses when TC spikes with similar preceding interspike interval were compared. Moreover, the relationship between the preceding interspike interval of the TC spike and postsynaptic response amplitude was not influenced by state. These data indicate that TC synaptic transmission and dynamics are highly conserved across different states of alertness and that observed state-related changes in receptive field properties that occur at the cortical level result from other mechanisms.

Hippocampal dysfunction during aging II: deficits on the radial-arm maze.

Middle-aged and aged rats received dorsal hippocampal lesions before performance was evaluated on the radial-arm maze. The maze task contained simultaneous spatial working memory and visually cued reference memory components. Both middle-aged and aged rats that received lesions committed more errors of both types than sham-operated rats. Moreover, an age-related deficit was found for working and reference memory errors. After 14 sessions of training, a probe session revealed that: (a) middle-aged sham rats relied on spatial cues, (b) middle-aged lesioned rats employed the visual cues at the ends of the maze arms, (c) aged sham rats relied predominately on spatial information, (d) aged lesioned rats could not use spatial information or the visual cues at the ends of the maze arms. The additive effect of lesion and age suggests continued reliance on the hippocampus despite age-related deficits in its functioning. These data are suggestive of reduction in flexible cue utilization during aging, resulting paradoxically in more dependence on the hippocampus for aged rats than younger animals.

The Impact of an LGNd Impulse on the Awake Visual Cortex: Synaptic Dynamics and the Sustained/Transient Distinction

We used spike-triggered current source-density analysis to examine axonal and postsynaptic currents generated in the visual cortex of awake rabbits by spontaneous spikes of individual sustained and transient dorsal lateral geniculate nucleus (LGNd) neurons. Using these data, we asked whether sustained/transient sensory responses are related to short-term synaptic dynamics at the thalamocortical synapse. Most sustained (34 of 40) and transient (24 of 25) neurons generated axonal and monosynaptic responses in layer 4 and/or 6 of the aligned cortical domain, with input from transient neurons arriving ∼0.3 ms earlier and 100–200 μm deeper. Postsynaptic cortical responses generated by both thalamic cell classes were reduced in amplitude after a preceding impulse and slowly recovered over a period of >750 ms. We interpret this to reflect interval-dependent recovery from chronic depression at the thalamocortical synapse, caused by significant spontaneous firing of LGNd cells (∼8 Hz). Surprisingly, postsynaptic cortical responses generated by spontaneous spikes of sustained thalamic neurons were more depressed than those of transient neurons. This difference was seen both in layers 4 and 6. The depression saturated rapidly with multiple preceding impulses, and postsynaptic responses generated by sustained neurons during maintained visual stimulation remained sufficiently robust to allow a sustained flow of information to the cortex. Our results indicate a relationship between the sensory response properties of thalamic neurons and the short-term dynamics of their synapses, and suggest that cortical recipients of sustained and transient thalamic inputs will differ considerably in their response modulation by prior impulse activity.

Dendritic Backpropagation and the State of the Awake Neocortex

The spread of somatic spikes into dendritic trees has become central to models of dendritic integrative properties and synaptic plasticity. However, backpropagating action potentials (BPAPs) have been studied mainly in slices, in which they are highly sensitive to multiple factors such as firing frequency and membrane conductance, raising doubts about their effectiveness in the awake behaving brain. Here, we examine the spatiotemporal characteristics of BPAPs in layer 5 pyramidal neurons in the visual cortex of adult, awake rabbits, in which EEG-defined brain states ranged from alert vigilance to drowsy/inattention, and, in some cases, to light sleep. To achieve this, we recorded extracellular spikes from layer 5 pyramidal neurons and field potentials above and below these neurons using a 16-channel linear probe, and applied methods of spike-triggered current source-density analysis to these records (Buzsáki and Kandel, 1998; Swadlow et al., 2002). Precise retinotopic alignment of superficial and deep cortical sites was used to optimize alignment of the recording probe with the axis of the apical dendrite. During the above network states, we studied BPAPs generated spontaneously, antidromically (from corticotectal neurons), or via intense synaptic drive caused by natural visual stimulation. Surprisingly, the invasion of BPAPs as far as 800 μm from the soma was little affected by the network state and only mildly attenuated by high firing frequencies. These data reveal that the BPAP is a robust and highly reliable property of neocortical apical dendrites. These events, therefore, are well suited to provide crucial signals for the control of synaptic plasticity during information-processing brain states.

Getting Drowsy? Alert/Nonalert Transitions and Visual Thalamocortical Network Dynamics

The effects of different EEG brain states on spontaneous firing of cortical populations are not well understood. Such state shifts may occur frequently under natural conditions, and baseline firing patterns can impact neural coding (e.g., signal-to-noise ratios, sparseness of coding). Here, we examine the effects of spontaneous transitions from alert to nonalert awake EEG states in the rabbit visual cortex (5 s before and after the state-shifts). In layer 4, we examined putative spiny neurons and fast-spike GABAergic interneurons; in layer 5, we examined corticotectal neurons. We also examined the behavior of retinotopically aligned dorsal lateral geniculate nucleus (LGNd) neurons, usually recorded simultaneously with the above cortical populations. Despite markedly reduced firing and sharply increased bursting in the LGNd neurons following the transition to the nonalert state, little change occurred in the spiny neurons of layer 4. However, fast-spike neurons of layer 4 showed a paradoxical increase in firing rates as thalamic drive decreased in the nonalert state, even though some of these cells received potent monosynaptic input from the same LGNd neurons whose rates were reduced. The firing rates of corticotectal neurons of layer 5, similarly to spiny cells of layer 4, were not state-dependent, but these cells did become more bursty in the nonalert state, as did the fast-spike cells. These results show that spontaneous firing rates of midlayer spiny populations are remarkably conserved following the shift from alert to nonalert states, despite marked reductions in excitatory thalamic drive and increased activity in local fast-spike inhibitory interneurons.

The Impact of a Corticotectal Impulse on the Awake Superior Colliculus

Corticotectal (CTect) neurons of layer 5 are large and prominent elements of mammalian visual cortex, with thick apical dendrites that ascend to layer 1, “intrinsically bursting” membrane properties, and fast-conducting descending axons that terminate in multiple subcortical domains. These neurons comprise a major output pathway of primary visual cortex, but virtually nothing is known about the synaptic influence of single CTect impulses on the superior colliculus (SC). Here, we examine the distribution of monosynaptic currents generated in the superficial SC by spontaneous impulses of single CTect neurons. We do this by recording the spikes of CTect neurons and the field potentials that they generate through the depths of the SC. Methods of spike-triggered averaging and current source density analysis are then applied to these data. We show, in fully awake rabbits, that single CTect impulses generate potent, fast-rising monosynaptic currents in the SC similar to those generated in sensory cortex by specific thalamic afferents. These currents are focal in depth, precisely retinotopic, and highly dependent on the conduction velocity of the CTect axon. Moreover, we show that CTect synapses, like thalamocortical synapses, suffer a chronic state of depression in awake subjects that is modulated by preceding interspike interval. However, CTect neurons generated few “bursts,” and postsynaptic responses in the SC were not significantly influenced by a shift from alert to an inattentive state (indicated by hippocampal EEG). Together, our results suggest that single CTect neurons may resemble thalamocortical neurons in their ability to serve as potent “drivers” of postsynaptic targets.

Heterosynaptic plasticity induced by intracellular tetanization in layer 2/3 pyramidal neurons in rat auditory cortex

Key points summary  •  Learning systems equipped with Hebbian‐type associative plasticity are prone to runaway dynamics of synaptic weights and lack mechanisms for synaptic competition; these problems can be resolved by heterosynaptic plasticity: changes at synapses which were not active during the induction. •  We show that in layer 2/3 pyramidal neurons from auditory cortex a purely postsynaptic challenge, intracellular tetanization, can induce heterosynaptic plasticity; similar to visual cortex, plasticity direction depends on initial properties of synapses: inputs with initially low release probability tend to potentiate, while those with initially high release probability tend to depress. •  Induction of heterosynaptic plasticity requires intracellular Ca2+ rise and its maintenance involves presynaptic changes, which depend on the nitric oxide signalling pathway. •  We conclude that heterosynaptic plasticity is a common property of supragranular pyramidal neurons mediating cortico‐cortical connections in both auditory and visual cortices; it may serve as a mechanism of synaptic weight normalization and synaptic competition in these cortical regions.

Functional Consequences of Neuronal Divergence Within the Retinogeniculate Pathway

The neuronal connections from the retina to the dorsal lateral geniculate nucleus (dLGN) are characterized by a high specificity. Each retinal ganglion cell diverges to connect to a small group of geniculate cells and each geniculate cell receives input from a small number of retinal ganglion cells. Consistent with the high specificity of the connections, geniculate cells sharing input from the same retinal afferent are thought to have very similar receptive fields. However, the magnitude of the receptive-field mismatches, which has not been systematically measured across the different cell types in dLGN, seems to be in contradiction with the functional anatomy of the Y visual pathway: Y retinal afferents in the cat diverge into two geniculate layers (A and C) that have Y geniculate cells (Y(A) and Y(C)) with different receptive-field sizes, response latencies, nonlinearity of spatial summation, and contrast sensitivity. To better understand the functional consequences of retinogeniculate divergence, we recorded from pairs of geniculate cells that shared input from a common retinal afferent across layers and within the same layer in dLGN. We found that nearly all cell pairs that shared retinal input across layers had Y-type receptive fields of the same sign (i.e., both on-center) that overlapped by >70%, but frequently differed in size and response latency. The receptive-field mismatches were relatively small in value (receptive-field size ratio <5; difference in peak response <5 ms), but were robustly correlated with the strength of the synchronous firing generated by the shared retinal connections (R(2) = 0.75). On average, the percentage of geniculate spikes that could be attributed to shared retinal inputs was about 10% for all cell-pair combinations studied. These results are used to provide new estimates of retinogeniculate divergence for different cell classes.

The Effects of Aging and Dorsal Hippocampal Lesions: Performance on Spatial and Nonspatial Comparable Versions of the Water Maze☆

Aged intact and young hippocampal-lesioned rats show similar deficits on the spatial water maze. However, this does not necessitate that the source of these deficits in the aged animals is due to hippocampal damage. These water maze deficits may arise from other aging factors such as changes in thermoregulation, muscle fatigue, swim ability, and response to stress. Consequently, it is imperative to examine the performance of aged rats on a comparable nonhippocampal version of this task. Past attempts to develop a hippocampus-independent version of the water maze were confounded because these tasks were easier (i.e., the rats spent much less time swimming in the water) than the spatial versions of the task. The current study examined performance on a hippocampus-independent task comparable in difficulty to the spatial water one. Middle-aged (16-m) and old (25-m) male F344 rats were given sham or dorsal hippocampus lesions and tested on both a spatial and a nonspatial water maze. The middle-aged rats with hippocampal lesions were impaired on the spatial task but not on the nonspatial task. Conversely, aged animals showed a similar impairment on both types of water maze tasks. Additionally, hippocampal lesions exacerbated the age-related impairment on both tasks. These findings indicate that caution must be used when interpreting the results of water maze tasks for aged animals.

Brain State Effects on Layer 4 of the Awake Visual Cortex

Awake mammals can switch between alert and nonalert brain states hundreds of times per day. Here, we study the effects of alertness on two cell classes in layer 4 of primary visual cortex of awake rabbits: presumptive excitatory “simple” cells and presumptive fast-spike inhibitory neurons (suspected inhibitory interneurons). We show that in both cell classes, alertness increases the strength and greatly enhances the reliability of visual responses. In simple cells, alertness also increases the temporal frequency bandwidth, but preserves contrast sensitivity, orientation tuning, and selectivity for direction and spatial frequency. Finally, alertness selectively suppresses the simple cell responses to high-contrast stimuli and stimuli moving orthogonal to the preferred direction, effectively enhancing mid-contrast borders. Using a population coding model, we show that these effects of alertness in simple cells—enhanced reliability, higher gain, and increased suppression in orthogonal orientation—could play a major role at increasing the speed of cortical feature detection.