We recently demonstrated that CD8؉ T cells could block herpes simplex virus type 1 (HSV-1) reactivation from latency in ex vivo trigeminal ganglion (TG) cultures without destroying the infected neurons. Here we establish that CD8؉ T-cell prevention of HSV-1 reactivation from latency is mediated at least in part by gamma interferon (IFN-␥). We demonstrate that IFN-␥ was produced in ex vivo cultures of dissociated latently infected TG by CD8 ؉ T cells that were present in the TG at the time of excision. Depletion of CD8 ؉ T cells or neutralization of IFN-␥ significantly enhanced the rate of HSV-1 reactivation from latency in TG cultures. When TG cultures were treated with acyclovir for 4 days to insure uniform latency, supplementation with recombinant IFN-␥ blocked HSV-1 reactivation in 80% of cultures when endogenous CD8 ؉ T cells were present and significantly reduced and delayed HSV-1 reactivation when CD8 ؉ T cells or CD45 ؉ cells were depleted from the TG cultures. The effectiveness of recombinant IFN-␥ in blocking HSV-1 reactivation was lost when its addition to TG cultures was delayed by more than 24 h after acyclovir removal. We propose that when the intrinsic ability of neurons to inhibit HSV-1 gene expression is compromised, HSV-specific CD8 ؉ T cells are rapidly mobilized to produce IFN-␥ and perhaps other antiviral cytokines that block the viral replication cycle and maintain the viral genome in a latent state.Following primary infection of epithelial surfaces, herpes simplex virus type 1 (HSV-1) gains access to the termini of sensory neurons, is transported in a retrograde direction to the neuron cell bodies in sensory ganglia, replicates, spreads to other neurons, and establishes a lifelong latent infection in a portion of the neurons. Recurrent HSV-1 disease results from reactivation of latent HSV-1 in sensory neurons followed by anterograde axonal transport to epithelial or epidermal surfaces. Therefore, treatments that block reactivation of HSV-1 from latency could effectively prevent recurrent disease in the face of latent infection. The long-term retention of CD8 ϩ T cells and production of the cytokine gamma interferon (IFN-␥) in the latently infected trigeminal ganglion (TG) suggest a possible role for the immune system in controlling HSV-1 reactivation from latency (4,10,16,20).Ganglionic latency is classically defined as retention of HSV-1 genomes in neurons in the absence of virion production. The definition of latency at the molecular level is currently evolving. Clearly, a family of transcripts called latencyassociated transcripts is produced in abundance in at least a portion of latently infected neurons (6, 7). In addition, transcripts for the HSV-1 ␣ (immediate-early) gene, infected cell protein 4 (ICP4), and ␤ (early) gene thymidine kinase were detected in low abundance in latently infected murine sensory ganglia (13). Most studies have failed to detect latency-associated transcript translation products, and the production of any viral proteins in latently infected neurons is currentl...

Although there are many perceptual theories that posit particular maturational profiles in higher-order (i.e., cortical) multisensory regions, our knowledge of multisensory development is primarily derived from studies of a midbrain structure, the superior colliculus. Therefore, the present study examined the maturation of multisensory processes in an area of cat association cortex [i.e., the anterior ectosylvian sulcus (AES)] and found that these processes are rudimentary during early postnatal life and develop only gradually thereafter. The AES comprises separate visual, auditory, and somatosensory regions, along with many multisensory neurons at the intervening borders between them. During early life, sensory responsiveness in AES appears in an orderly sequence. Somatosensory neurons are present at 4 weeks of age and are followed by auditory and multisensory (somatosensory-auditory) neurons. Visual neurons and visually responsive multisensory neurons are first seen at 12 weeks of age. The earliest multisensory neurons are strikingly immature, lacking the ability to synthesize the cross-modal information they receive. With postnatal development, multisensory integrative capacity matures. The delayed maturation of multisensory neurons and multisensory integration in AES suggests that the higher-order processes dependent on these circuits appear comparatively late in ontogeny.

It has recently been demonstrated that the maturation of normal multisensory circuits in the cortex of the cat takes place over an extended period of postnatal life. Such a finding suggests that the sensory experiences received during this time may play an important role in this developmental process. To test the necessity of sensory experience for normal cortical multisensory development, cats were raised in the absence of visual experience from birth until adulthood, effectively precluding all visual and visual-nonvisual multisensory experiences. As adults, semichronic single-unit recording experiments targeting the anterior ectosylvian sulcus (AES), a well-defined multisensory cortical area in the cat, were initiated and continued at weekly intervals in anesthetized animals. Despite having very little impact on the overall sensory representations in AES, dark-rearing had a substantial impact on the integrative capabilities of multisensory AES neurons. A significant increase was seen in the proportion of multisensory neurons that were modulated by, rather than driven by, a second sensory modality. More important, perhaps, there was a dramatic shift in the percentage of these modulated neurons in which the pairing of weakly effective and spatially and temporally coincident stimuli resulted in response depressions. In normally reared animals such combinations typically give rise to robust response enhancements. These results illustrate the important role sensory experience plays in shaping the development of mature multisensory cortical circuits and suggest that dark-rearing shifts the relative balance of excitation and inhibition in these circuits.

Carriere BN, Royal DW, Wallace MT. Spatial heterogeneity of cortical receptive fields and its impact on multisensory interactions. J Neurophysiol 99: 2357-2368, 2008. First published February 20, 2008 doi:10.1152/jn.01386.2007. Investigations of multisensory processing at the level of the single neuron have illustrated the importance of the spatial and temporal relationship of the paired stimuli and their relative effectiveness in determining the product of the resultant interaction. Although these principles provide a good first-order description of the interactive process, they were derived by treating space, time, and effectiveness as independent factors. In the anterior ectosylvian sulcus (AES) of the cat, previous work hinted that the spatial receptive field (SRF) architecture of multisensory neurons might play an important role in multisensory processing due to differences in the vigor of responses to identical stimuli placed at different locations within the SRF. In this study the impact of SRF architecture on cortical multisensory processing was investigated using semichronic single-unit electrophysiological experiments targeting a multisensory domain of the cat AES. The visual and auditory SRFs of AES multisensory neurons exhibited striking response heterogeneity, with SRF architecture appearing to play a major role in the multisensory interactions. The deterministic role of SRF architecture was tightly coupled to the manner in which stimulus location modulated the responsiveness of the neuron. Thus multisensory stimulus combinations at weakly effective locations within the SRF resulted in large (often superadditive) response enhancements, whereas combinations at more effective spatial locations resulted in smaller (additive/subadditive) interactions. These results provide important insights into the spatial organization and processing capabilities of cortical multisensory neurons, features that may provide important clues as to the functional roles played by this area in spatially directed perceptual processes.