No two roses smell exactly alike, but our brain accurately bundles these variations into a single percept `rose'. We found that ensembles of rat olfactory bulb neurons decorrelate complex mixtures that vary by as little as a single missing component, whereas olfactory (piriform) cortical neural ensembles perform pattern completion in response to an absent component, essentially filling in the missing information and allowing perceptual stability. This piriform cortical ensemble activity predicts olfactory perception.The need for perceptual discrimination must be balanced with the need for perceptual stability. Without an ability to ignore some differences between input patterns, nearly all experiences would be unique, with each presentation of a similar stimulus being devoid of previously acquired associations and meaning. Computational modeling and experimental data suggest that some cortical circuits balance discrimination and stability through the network emergent functions of pattern separation and pattern completion 1-5 . Simply put, pattern separation allows partially overlapping input patterns to be decorrelated and processed as being distinct. Pattern completion is a memory-based phenomenon 6 that allows degraded input patterns to be compared to existing templates and, if they are sufficiently close to those templates, `completed' and processed as a match. These processes have been examined in some detail in the hippocampal formation, where slight changes in the spatial distribution of visual cues can be completed to promote stability in hippocampal neuronal place fields and presumably stability in spatial maps and perception. With further change or degradation in the visual spatial patterns, hippocampal place fields shift, presumably along with spatial perception. In olfaction, the need for pattern separation and completion is particularly intense, as most natural odors derive from odorant mixtures, evoking complex spatiotemporal patterns of olfactory sensory neuron and olfactory bulb activity 7 . Given this complexity, it is rare for a given stimulus to always have the exact same components in the exact same proportions, yet it is possible for a noisy or degraded stimulus to reliably evoke a stable percept. On the other hand, if the component makeup changes sufficiently, discrimination ensues. Evidence for pattern completion would be consistent with the view of olfactory perception as an object-oriented sense, where sensation , from which components were removed (for example, 10c-1 (10 components with 1 removed), 10c-2 (10 components with 2 removed), etc.) or replaced (10cR1, 10cR2, etc). This core mixture and its subsets were repeatedly presented during testing, and, given the speed at which cortical units become familiarized to odor mixtures even under anesthesia 13 , it was assumed they were familiar to the rats. We examined aPCX single units responding to the odorant mixtures (two typical examples are shown in Fig. 1a). These units responded to several different mixture combinations, and a...

Objective Anesthetics have been linked to widespread neuronal cell death in neonatal animals. Epidemiological human studies have associated early childhood anesthesia with long-term neurobehavioral abnormalities, raising substantial concerns that anesthetics may cause similar cell death in young children. However, key aspects of the phenomenon remain unclear, such as why certain neurons die, whereas immediately adjacent neurons are seemingly unaffected, and why the immature brain is exquisitely vulnerable, whereas the mature brain seems resistant. Elucidating these questions is critical for assessing the phenomenon’s applicability to humans, defining the susceptible age, predicting vulnerable neuronal populations, and devising mitigating strategies. Methods This study examines the effects of anesthetic exposure on late- and adult-generated neurons in newborn, juvenile, and adult mice, and characterizes vulnerable cells using birth-dating and immunohistochemical techniques. Results We identify a critical period of cellular developmental during which neurons are susceptible to anesthesia-induced apoptosis. Importantly, we demonstrate that anesthetic neurotoxicity can extend into adulthood in brain regions with ongoing neurogenesis, such as dentate gyrus and olfactory bulb. Interpretation Our findings suggest that anesthetic vulnerability reflects the age of the neuron, not the age of the organism, and therefore may potentially not only be relevant to children but also to adults undergoing anesthesia. This observation further predicts differential heightened regional vulnerability to anesthetic neuroapoptosis to closely follow the distinct regional peaks in neurogenesis. This knowledge may help guide neurocognitive testing of specific neurological domains in humans following exposure to anesthesia, dependent on the individual’s age during exposure.

Purpose Aberrant plastic changes among adult-generated hippocampal dentate granule cells are hypothesized to contribute to the development of temporal lobe epilepsy. Changes include formation of basal dendrites projecting into the dentate hilus. Innervation of these processes by granule cell mossy fiber axons leads to the creation of recurrent excitatory circuits within the dentate. The destabilizing effect of these recurrent circuits may contribute to hyperexcitability and seizures. While basal dendrites have been identified in status epilepticus models of epilepsy associated with increased neurogenesis, whether similar changes are present in the intrahippocampal kainic acid model of epilepsy – which is associated with reduced neurogenesis – is not known. Methods In the present study, we used Thy1-YFP-expressing transgenic mice to determine whether hippocampal dentate granule cells develop hilar-projecting basal dendrites in the intrahippocampal kainic acid model. Brain sections were examined two weeks after treatment. Tissue was also examined using ZnT-3 immunostaining for granule cell mossy fiber terminals to assess recurrent connectivity. Adult-neurogenesis was assessed using the proliferative marker Ki-67 and the immature granule cell marker calretinin. Key Findings Significant numbers of cells with basal dendrites were found in this model, but their structure was distinct from basal dendrites seen in other epilepsy models, often ending in complex tufts of short branches and spines. Even more unusual, a subset of cells with basal dendrites had an inverted appearance, completely lacking apical dendrites. Spines on basal dendrites were found to be apposed to ZnT-3 immunoreactive puncta, suggestive of recurrent mossy fiber input. Finally, YFP-expressing abnormal granule cells did not colocalize Ki-67 or calretinin, indicating that these cells were more than a few weeks old, but were found almost exclusively in close proximity to the neurogenic subgranular zone, where the youngest granule cells are located. Significance Recent studies have demonstrated in other models of epilepsy that dentate pathology develops following the aberrant integration of immature, adult-generated granule cells. Given these findings, one might predict that the intrahippocampal kainic acid model of epilepsy, which is associated with a dramatic reduction in adult neurogenesis, would not exhibit these changes. Here, we demonstrate that hilar basal dendrites are a common feature of this model, with the abnormal cells likely resulting from the disruption of juvenile granule cell born in the weeks prior to the insult. These studies demonstrate that post-injury neurogenesis is not required for the accumulation of large numbers of abnormal granule cells.

The present study confirms the findings of previous studies showing peak vulnerability to anaesthesia-induced neuronal cell death in the newborn forebrain. It also shows sustained susceptibility into adulthood in areas of continued neurogenesis, substantially expanding the previously observed age of vulnerability. The differential windows of vulnerability among brain regions, which closely follow regional peaks in neurogenesis, may explain the heightened vulnerability of the developing brain because of its increased number of immature neurones.

We confirm previous findings of sevoflurane-induced neuronal injury. Dexmedetomidine, even in the highest dose, did not cause similar injury, but provided lesser degrees of anaesthesia and pain control. No mitigation of sevoflurane-induced injury was observed with dexmedetomidine supplementation, suggesting that future studies should focus on anaesthetic-sparing effects of dexmedetomidine, rather than injury-preventing effects.

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Background Exposure to isoflurane increases apoptosis among postnatally generated hippocampal dentate granule cells. These neurons play important roles in cognition and behavior, so their permanent loss could explain deficits after surgical procedures. Methods To determine whether developmental anesthesia exposure leads to persistent deficits in granule cell numbers, a genetic fate-mapping approach to label a cohort of postnatally generated granule cells in Gli1-CreERT2::GFP bitransgenic mice was utilized. Green fluorescent protein (GFP) expression was induced on postnatal day 7 (P7) to fate map progenitor cells, and mice were exposed to 6 h of 1.5% isoflurane or room air 2 weeks later (P21). Brain structure was assessed immediately after anesthesia exposure (n = 7 controls and 8 anesthesia-treated mice) or after a 60-day recovery (n = 8 controls and 8 anesthesia-treated mice). A final group of C57BL/6 mice was exposed to isoflurane at P21 and examined using neurogenesis and cell death markers after a 14-day recovery (n = 10 controls and 16 anesthesia-treated mice). Results Isoflurane significantly increased apoptosis immediately after exposure, leading to cell death among 11% of GFP-labeled cells. Sixty days after isoflurane exposure, the number of GFP-expressing granule cells in treated animals was indistinguishable from control animals. Rates of neurogenesis were equivalent among groups at both 2 weeks and 2 months after treatment. Conclusions These findings suggest that the dentate gyrus can restore normal neuron numbers after a single, developmental exposure to isoflurane. The authors’ results do not preclude the possibility that the affected population may exhibit more subtle structural or functional deficits. Nonetheless, the dentate appears to exhibit greater resiliency relative to nonneurogenic brain regions, which exhibit permanent neuron loss after isoflurane exposure.

Background-Exposure to isoflurane increases apoptosis among postnatally-generated hippocampal dentate granule cells. These neurons play important roles in cognition and behavior, so their permanent loss could explain deficits following surgical procedures.