Peptide Cotransmitters as Dynamic, Intrinsic Modulators of Network Activity

Neurons can contain both neuropeptides and “classic” small molecule transmitters. Much progress has been made in studies designed to determine the functional significance of this arrangement in experiments conducted in invertebrates and in the vertebrate autonomic nervous system. In this review article, we describe some of this research. In particular, we review early studies that related peptide release to physiological firing patterns of neurons. Additionally, we discuss more recent experiments informed by this early work that have sought to determine the functional significance of peptide cotransmission in the situation where peptides are released from neurons that are part of (i.e., are intrinsic to) a behavior generating circuit in the CNS. In this situation, peptide release will presumably be tightly coupled to the manner in which a network is activated. For example, data obtained in early studies suggest that peptide release will be potentiated when behavior is executed rapidly and intervals between periods of neural activity are relatively short. Further, early studies demonstrated that when neural activity is maintained, there are progressive changes (e.g., increases) in the amount of peptide that is released (even in the absence of a change in neural activity). This suggests that intrinsic peptidergic modulators in the CNS are likely to exert effects that are manifested dynamically in an activity-dependent manner. This type of modulation is likely to differ markedly from the modulation that occurs when a peptide hormone is present at a relatively fixed concentration in the blood

The Complement of Projection Neurons Activated Determines the Type of Feeding Motor Program in Aplysia

Multiple projection neurons are often activated to initiate behavior. A question that then arises is, what is the unique functional role of each neuron activated? We address this issue in the feeding system of Aplysia. Previous experiments identified a projection neuron [cerebral buccal interneuron 2 (CBI-2)] that can trigger ingestive motor programs but only after it is repeatedly stimulated, i.e., initial programs are poorly defined. As CBI-2 stimulation continues, programs become progressively more ingestive (repetition priming occurs). This priming results, at least in part, from persistent actions of peptide cotransmitters released from CBI-2. We now show that in some preparations repetition priming does not occur. There is no clear seasonal effect; priming and non-priming preparations are encountered throughout the year. CBI-2 is electrically coupled to a second projection neuron, cerebral buccal interneuron 3 (CBI-3). In preparations in which priming does not occur, we show that ingestive activity is generated when CBI-2 and CBI-3 are coactivated. Programs are immediately ingestive, i.e., priming is not necessary, and a persistent state is not induced. Our data suggest that dynamic changes in the configuration of activity can vary and be determined by the complement of projection neurons that trigger activity

More Than Forty Prominent Economists Urge Supreme Court to Allow EPA to Consider Costs and Consequences of Clean Air Regulations

More than forty prominent economists filed a Friend of the Court brief with the Supreme Court, asking the justices to overturn a lower court ruling that the Environmental Protection Agency (EPA) may not take into account the costs of regulations when setting standards under the Clean Air Act. Calling the lower court ruling "economically unsound," the economists argued that the EPA "should be allowed to consider explicitly the full consequences" of regulatory decisions, including costs, benefits, and any other relevant facts. In their Amici Curiae brief, the economists contended that the "plain aim" of the Clean Air Act "is protecting the public health&quo.t; That aim, they said, "is unlikely to be achieved without, at least, an implicit balancing of benefits and costs." The Supreme Court filing was organized by the American Enterprise Institute-Brookings Joint Center for Regulatory Studies. The bipartisan group of economists signing the brief included three Nobel laureates, seven former chairmen of the President's Council of Economic Advisers, and two former directors of the White House Office of Management and Budget. The case, American Trucking Association v. Carol M. Browner, Administrator of the Environmental Protection Agency , was appealed to the Supreme Court after a Federal Court in Washington D.C. ruled that the EPA was not permitted to consider costs in setting regulatory standards for enforcing the Clean Air Act. "We believe it would be imprudent for the EPA to ignore costs totally, particularly given their magnitude in this case," the economists stated in the brief. "The EPA estimates that those [clean air] standards could cost on the order of $50 billion annually." The brief argued, "Not considering costs makes it difficult to set a defensible standard, especially when there is no threshold below which health risks disappear." Ignoring costs, the economists said, "could lead to a decision to set the standard at zero pollution," which would threaten "the very economic prosperity on which public health primarily depends." The economists declared: "The importance of this issue cannot be overstated. Both direct benefits and costs of environmental, health, and safety regulations are substantial, estimated to be several hundred billion dollars annually." If the Supreme Court overturns the lower court ruling and allows the EPA to consider costs in establishing clear air regulations, the brief argued, it would be "a historic moment in the making of regulatory policy."Environment, Other Topics

Two Distinct Mechanisms Mediate Potentiating Effects of Depolarization on Synaptic Transmission

Two distinct mechanisms mediate potentiating effects of depolarization on synaptic transmission. Recently there has been renewed interest in a type of plasticity in which a neuron's somatic membrane potential influences synaptic transmission. We study mechanisms that mediate this type of control at a synapse between a mechanoafferent, B21, and B8, a motor neuron that receives chemical synaptic input. Previously we demonstrated that the somatic membrane potential determines spike propagation within B21. Namely, B21 must be centrally depolarized if spikes are to propagate to an output process. We now demonstrate that this will occur with central depolarizations that are only a few millivolts. Depolarizations of this magnitude are not, however, sufficient to induce synaptic transmission to B8. B21-induced postsynaptic potentials (PSPs) are only observed if B21 is centrally depolarized by ≥10 mV. Larger depolarizations have a second impact on B21. They induce graded changes in the baseline intracellular calcium concentration that are virtually essential for the induction of chemical synaptic transmission. During motor programs, subthreshold depolarizations that increase calcium concentrations are observed during one of the two antagonistic phases of rhythmic activity. Chemical synaptic transmission from B21 to B8 is, therefore, likely to occur in a phase-dependent manner. Other neurons that receive mechanoafferent input are electrically coupled to B21. Differential control of spike propagation and chemical synaptic transmission may, therefore, represent a mechanism that permits selective control of afferent transmission to different types of neurons contacted by B21. Afferent transmission to neurons receiving chemical synaptic input will be phase specific, whereas transmission to electrically coupled followers will be phase independent