Functional impact of cerebral connections

Cerebral networks are complex sets of connections that resemble a ladder-like web of multiple parallel feedforward, lateral, and feedback connections. This static anatomical description has been pivotal in guiding our understanding of signal processing within cerebral networks. However, measures on both magnitude and functional significance of connections are extremely limited. Here, we compare the anatomically defined strengths of a set of cerebral pathways emerging from the visual middle suprasylvian (MS) cortex of the cat with measures of the functional impact the same region has over distant sites. These functional measures were obtained by analyzing the local and distant effects of MS cooling deactivation on deoxyglucose uptake. Relative to major efferent projections from MS cortex that have a strong influence, projections to early visual processing stages have weaker functional influences than predicted from the anatomy. For higher processing stages, the converse holds: projections from MS cortex have stronger functional influence than predicted from the anatomy. We conclude that these and future functional measures, obtained using the same combination of techniques, will furnish fundamental, new information that complements and extends current models of static cerebral networks, and lead to more realistic models of cerebral network function and component interactions.

Growth of new brainstem connections in adult monkeys with massive sensory loss

Somatotopic maps in the cortex and the thalamus of adult monkeys and humans reorganize in response to altered inputs. After loss of the sensory afferents from the forelimb in monkeys because of transection of the dorsal columns of the spinal cord, therapeutic amputation of an arm or transection of the dorsal roots of the peripheral nerves, the deprived portions of the hand and arm representations in primary somatosensory cortex (area 3b), become responsive to inputs from the face and any remaining afferents from the arm. Cortical and subcortical mechanisms that underlie this reorganization are uncertain and appear to be manifold. Here we show that the face afferents from the trigeminal nucleus of the brainstem sprout and grow into the cuneate nucleus in adult monkeys after lesions of the dorsal columns of the spinal cord or therapeutic amputation of an arm. This growth may underlie the large-scale expansion of the face representation into the hand region of somatosensory cortex that follows such deafferentations.

Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis

Independent studies indicate that expression of sialylated fucosylated mucins by human carcinomas portends a poor prognosis because of enhanced metastatic spread of tumor cells, that carcinoma metastasis in mice is facilitated by formation of tumor cell complexes with blood platelets, and that metastasis can be attenuated by a background of P-selectin deficiency or by treatment with heparin. The effects of heparin are not primarily due to its anticoagulant action. Other explanations have been suggested but not proven. Here, we bring together all these unexplained and seemingly disparate observations, showing that heparin treatment attenuates tumor metastasis in mice by inhibiting P-selectin-mediated interactions of platelets with carcinoma cell-surface mucin ligands. Selective removal of tumor mucin P-selectin ligands, a single heparin dose, or a background of P-selectin deficiency each reduces tumor cell-platelet interactions in vitro and in vivo. Although each of these maneuvers reduced the in vivo interactions for only a few hours, all markedly reduce long-term organ colonization by tumor cells. Three-dimensional reconstructions by using volume-rendering software show that each situation interferes with formation of the platelet “cloak” around tumor cells while permitting an increased interaction of monocytes (macrophage precursors) with the malignant cells. Finally, we show that human P-selectin is even more sensitive to heparin than mouse P-selectin, giving significant inhibition at concentrations that are in the clinically acceptable range. We suggest that heparin therapy for metastasis prevention in humans be revisited, with these mechanistic paradigms in mind.

Modular organization of intrinsic connections associated with spectral tuning in cat auditory cortex

Many response properties in primary auditory cortex (AI) are segregated spatially and organized topographically as those in primary visual cortex. Intensive study has not revealed an intrinsic, anatomical organizing principle related to an AI functional topography. We used retrograde anatomic tracing and topographic physiologic mapping of acoustic response properties to reveal long-range (≥1.5 mm) convergent intrinsic horizontal connections between AI subregions with similar bandwidth and characteristic frequency selectivity. This suggests a modular organization for processing spectral bandwidth in AI.

Enhancement of sensorimotor connections by conditioning-related stimulation in Aplysia depends upon postsynaptic Ca2+.

Classical conditioning of Aplysia's siphon-withdrawal reflex is thought to be due to a presynaptic mechanism-activity-dependent presynaptic facilitation of sensorimotor connections. Recent experiments with sensorimotor synapses in dissociated cell culture, however, provide an alternative cellular mechanism for classical conditioning-Hebbian long-term potentiation (LTP) of sensorimotor connections. Induction of Hebbian LTP of these connections is mediated by activation of N-methyl-D-aspartate-related receptors and requires the postsynaptic elevation of intracellular Ca2+. To determine whether the enhancement of sensorimotor synapses during classical conditioning in Aplysia-like LTP of sensorimotor synapses in culture-also depends upon the elevation of postsynaptic Ca2+, we carried out experiments involving the cellular analog of classical conditioning of siphon withdrawal. We examined changes in the strength of monosynaptic siphon sensorimotor connections in the abdominal ganglion of Aplysia following paired presentations of sensory neuron activation and tail nerve shock. This training regimen resulted in significant enhancement of the monosynaptic sensorimotor excitatory postsynaptic potential, as compared with the sensorimotor excitatory postsynaptic potential in preparations that received only test stimulation. Infusing the motor neuron with 1,2-bis(2-aminophenoxy)ethane-N,N-N',N'-tetraacetic acid, a specific chelator of intracellular Ca2+, prior to paired stimulation training blocked this synaptic enhancement. Our results implicate a postsynaptic, possibly Hebbian, mechanism in classical conditioning in Aplysia.