On the waterfront: Predictive and reactive regulatory descriptions of thirst and sodium appetite

Physiology& Behavior. Vol. 48, pp. 899-903. e Pergamon Press plc, 1990. Printed in the U.S.A.

0031-9384/90 $3.00 + .00

On the Waterfront: Predictive and Reactive Regulatory Descriptions of Thirst and Sodium Appetite I N E I L E. R O W L A N D 2

Department o f Psychology, University o f Florida, Gainesville, FL 32611-2065

ROWLAND, N. E. On the waterfront: Predictive and reactive regulatory descriptions of thirst and sodium appetite. PHYSIOL BEHAV 48(6) 899-903, 1990.--The concepts of homeostasis and regulation are discussed and examples are given in which current regulatory models of ingestive behavior inadequately predict or explain the observed phenomena. The implications of this for the choice of experimental paradigms, and the interpretation of neurobiological data obtained therein, are discussed. Paradigms that allow the expression of behavioral strategies and learned responses may be biologically more relevant than the more popular but highly constrained "physiologic" paradigms. Homeostasis

Regulation

Strategy

Thirst

Sodium appetite

THE explosive growth in the number and relative ease of performing various types of molecular analyses of biological tissues has progressively infiltrated studies of mechanism in ingestive behavior, as seen, for example, in the number and diversity of papers at this Congress. For the benefit of new colleagues whose primary expertise is in these molecular fields, but also as a reminder to some of us who once knew better, it is evident that there is not a corresponding abundance of ideas or concepts of ways in which functions devolve from these components, or how these functions are integrated together to produce behavior. This type of discrepancy is by no means unique to biobehavioral sciences, but presents challenges to develop new integrative concepts and constructs. It is necessary fast to appreciate that behavior, or what might constitute an explanation of behavior, can be approached at several different levels (Table 1). Most of the research presented at this Congress falls into the category of "the way it works." However, this should not overshadow but rather should complement the other levels at which we seek to explain ingestive behavior. A similar point has been made by Bunge (1) insofar as animals, and human beings in particular, span levels from global societies down to subatomic particles. Each of a variety of intermediate and hierarchical levels (e.g., cells, organs, "supersystems" such as CNS) need to interface with each other in order for science to present an adequate explanation of a phenomenon such as ingestive behavior. While the analytical or " t o p down" ap-

Nycthemeral rhythm

proach to a problem is fruitful insofar as it is relatively easy to generate and test hypotheses, the synthetic or "bottom u p " approach is also necessary. Bunge thus advocates a multilevel approach in which "every system should be studied at its own level as well as a component of a supersystem and as composed of lower level things." He also notes that "physiological psychology contributes powerfully to the synthesis . . . . " a viewpoint with which I concur. HOMEOSTASIS For over 50 years, the principal theoretical paradigm of our area has been homeostasis, the active regulation of certain variable(s) within limits conducive to optimal functioning. Davis (4) made a most important distinction between, on the one hand, the general use of the term homeostasis to explain motivated behavior and, on the other hand, using control systems theory and its associated regulatory mechanistic view to model motivated behavior. To some extent, this distinction is isomorphic with that of homeostasis as a description either of a behavioral state of affairs or as an internal constancy. The former exercise is uncontroversial, if we understand that homeostasis is a description rather than an explanation. The latter aspect is only one way in which internal homeostasis might be achieved. Hogan [(8), p. 19], discussing these same issues, has gone so far as to suggest that "it seems inappropriate to apply the concept of homeostasis to the analysis of motivational processes."

~This manuscript develops one of the themes from an address "Future studies of ingestive behavior: animal models, conceptual questions, and therapeutic applications" given at the Xth International Congress on the Physiology of Food and Fluid Intake, Pads, July 1989. This work was funded in part by the National Science Foundation (BNS 8909439). 2Send correspondance to this address, or by electronic mail to: rowland @ webb.psych.ufl.eda.

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TABLE 1 TYPES OF EXPLANATIONOF BEHAVIOR The animal behaves the way it does because . . . 1. of the way its ancestors evolved 2. of the way it developed 3a. of the way it responds to situation 3b. of the way it works 4. that behavior promotes survival

Some of these difficult problems in the analysis of feeding are considered by Collier and Johnson (3).

Adrenalectomy and Salt Appetite Evolutionary history Developmental history Motivation (causation) Physiology (causation) Function

From Sibly (25). In common with the concerns of Davis and Hogan, Weingarten (29) has considered three types of regulatory mechanism: negative feedback, anticipation/feedforward, and " adaptive control," all of which contribute to homeostasis (his examples are in relation to body energy and feeding). The third of these, adaptive control, may act at any or all of the levels of comparator (i.e., altering an effective set point), gain in the feedback loop, or output control mechanism of a simple negative feedback regulatory system. Weingarten also suggests that alimentary learning is manifest through changes in adaptive control. This concept is in some respects similar to Collier's (2) "house economist" whose function is to interface the needs of a "resident physiologist" with the outside world. Collier and Johnson (3) further address these issues in this volume. One key feature of any regulatory system is that in order to generate output (behavior) a deficit needs to be detected relative to a reference or normal value [see Davis (4) on the use, or misuse, of the term set point]. Critics of this type of model have noted instances in which ingestion occurs without any identifiable deficit, and some authors have used the term "nonhomeostatic" to describe such intake. As discussed by Davis (4), Hogan (8) and myself (15,16), this is not a particularly useful term because any and all ingestive behavior that promotes survival also subserves homeostasis. Fitzsimons (7) made a careful distinction between primary drinking, precipitated by identifiable physiologic deficits, and secondary drinking that occurs in the absence of such deficits but nonetheless may subserve longer term homeostatic function. The terms regulatory and nonregulatory drinking appear to be identical to primary and secondary, respectively, and refer to a process rather than a state. One way of articulating these distinctions was used in another context by Moore-Erie (10) and can be extrapolated to ingestive behavior (17). He distinguished between reactive homeostasis, which refers to restoring a system after it has become imbalanced, and predictive homeostasis, which may anticipate a recurrent imbalance and so prevent it from occurring. From the foregoing, I am no longer [cf. (17)] sure that homeostasis is the right term to use in this behavioral extrapolation; I will instead use the terms predictive and reactive regulation. Examples of predictive regulation include nycthemeral or seasonal changes in feeding and body weight, and many of the conditioned aspects that pervade the normal ingestion. The following four examples illustrate cases in which ingestive behavior does not conform to a simple feedback or "reactive regulatory" model. These examples, from my own work, use the simple systems of water and salt balance. Hydromineral systems are likely more amenable to homeostatic analysis because, from a physiologic standpoint they may be more tightly regulated than energy balance, and from a psychological perspective there are only a few commodities to consider compared with the cornucopia faced in analysis of feeding behavior.

Richter first described the salt appetite of adrenalectomized rats and explained this in terms of a regulatory behavioral process. In studying such animals, we noted that their ad lib intake of NaC1 solution was at least 80% nocturnal, despite the fact that daytime excretion of Na + was much higher than in adrenally intact controls (18). Thus, relative to these controls, adrenalectomized rats showed a greater negative Na + balance during the daytime but initiated little or no restorative behavior. During the night, their large sodium intake produced a correspondingly larger positive Na ÷ balance than in controls. The data clearly show that adrenalectomized rats self-sustain much larger oscillations in their sodium balance than controls. This is inconsistent with the simplest form of a reactive homeostatic model according to which a bout of behavior should occur each and every time a suprathreshold depletion of sodium occurred. At a minimum, a nycthemeral variable is gating the system. Insofar as salt appetite in adrenalectomized rats may be energized primarily by elevated levels of angiotensin II in brain (21), new hypotheses can be tested concerning the basis of this behavioral rhythm. At a more general level, most spontaneous salt intake in normal rats occurs at night, and so it is relevant to examine nycthemeral variations in candidate physiologic mechanisms. This point is reinforced in the next example.

Thirst Deficits After Brain Damage During the 1960's a detailed description and analysis was presented (6) of the deficits in drinking following lateral hypothalamic lesions in rats. This serves as an example of the types of deficits seen after a range of other types of central and peripheral damage (16). In brief, after a period of adipsia, these animals recover spontaneous drinking but remain unresponsive to experimental dehydration such as that induced by injection of hypertonic NaC1. It was concluded that, if the homeostatic mechanisms of drinking (osmotic and volumetric) were inoperative, then the recovered spontaneous drinking must be independent of these systems (6). I was surprised to discover that rats with lateral hypothalamic lesions that did not drink in brief tests after injection of NaCl (the "classic" result) nonetheless increased their intakes over the next 24 h (13). I then showed that they drank to injections or infusions of NaC1, as well as to salt in the food, but that their responses were exclusively nocturnal or, in blind rats, occurred only during the active phase of an endogenous 24-h oscillator (12-15). For example, when hypertonic NaCl was infused continuously for several days, the lesioned rats drank nothing by day (and so became relatively dehydrated) and drank excessively at night (relative to their baseline). Thus, the so-called regulatory or homeostatic drinking response is present, but only at certain times of day. The point here is that if we define primary drinking as that which occurs within a defined but brief period after a large, acutely induced disturbance at an abnormal time of day, then we are by definition excluding (and usually not looking for) other modes in which the regulation may be expressed. The behavior of lesioned animals is certainly less flexible than that of the intact animal who drinks frequently and quickly under all of the above situations but it does not lack all of the components of reactive regulatory drinking. Teitelbaum's (27) careful analysis of movement

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in lesioned animals has produced the important notion that allied reflexes both shape the direction of chains of action in intact organisms but also promote recovery of function from brain damage. Allied reflexes can be "unmasked" by the study of what lesioned animals can do, rather than what they cannot do. Applying this analysis to the present example, I suggest that nycthemeral rhythms either themselves function as, or work via, allied reflexes to facilitate nocturnal behaviors. In the present example, this is manifest as an exaggerated dependence on an internal clock in the lesioned animals. The general concept can also be applied to the previous example of salt appetite after adrenalectomy.

Sham Drinking In the sham-drinking preparation, most orally ingested fluid drains through an open fistula and postingestional effects are thereby minimized. Many aspects of sham feeding and drinking have been described, mostly using deprivation as a precipitating stimulus [e.g., (28)]. We asked whether either single or combined osmometfic and volumetric dehydrations (i,e., the primary drinking stimuli that have been most closely tied to primary or reactive regulatory models) would yield both independent and additive sham drinks (24). They did not. Rats that were 24-h water deprived showed a classic sham drink with intake on their f'wst open fistula shamdrinking trial of about 40 ml in 1 h, or 3 × that of a group with closed fistulas. Rats treated with either single or combined intracellular (NaC1) and extracellular (polyethylene glycol, PEG) dehydrating stimuli and run with the fistula open drank amounts similar to their closed fistula counterparts. Of particular interest is the fact that the combined NaCI + PEG stimulus produced the same intake (12 ml) in the closed fistula rats as did 24-h water deprivation. However, in the sham-drinking groups, while the intake after deprivation was about 40 ml, the intake after NaC1+ PEG was only about 12 ml. That is, the combined stimulus that was designed to mimic the physiologic state of deprivation was totally ineffective in supporting a sham drink. One interpretation of these data is that drinking to NaC1+ PEG does not depend upon postingestive factors, a conclusion that is precisely opposite to that predicted from reactive regulatory/negative feedback models! Clearly, more work is needed to understand more fully this effect and its implications for theory, but thus far the data argue that physiologic deficit is not a good predictor of drinking behavior in the absence of postingestional cues. Instead, some other aspect of deprivation (e.g., passage of time) is also important. (We have ruled out the obvious point that water-deprived rats eat less food by showing identical results in rats deprived of food prior to NaCl + PEG.) In fact, it is widely acknowledged that the performance of consummatory acts, in this case licking with associated taste cues, are sufficient reinforcement to maintain high levels of operant behavior. For example, sham drinking does not extinguish, and in fact may increase with experience (28). Rats will also exhibit air or cold-licking (9,11) as a function of fluid deprivation, a phenomenon that further demonstrates that neither taste nor postingestional effects are necessary to maintain licking. Conversely, when oral ingestion is precluded, such as with intragastric or venous self-administration of water via a bar-press operant, water intake is quite low and shows only modest "regulatory" modifiability (15). Additionally, the temperature of water influences the amount ingested in a regulatory drinking situation (5). These data imply deficit-driven mechanisms can have a deterministic role in drinking behavior, but that the timing and amounts of

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drinking are specified by many other mechanisms [see (3) for related arguments].

Salt Preference and Appetite In rats, but not in all mammals (19), both aldosterone and angiotensin II are able to act in synergy to produce intake of a concentrated solution of NaCI (salt appetite). It is logical to ask whether removal of these hormones reduces salt intake. Parenteral salt loads that rapidly produce physiologic repletion only slowly or incompletely reduce NaCI intake of sodium-depleted rats, but oral preloads are effective (19). Antagonists of either aldosterone or angiotensin II each are able to reduce, and in combination abolish, NaC1 intake following sodium depletion (22). Why, then, are parenteral loads that presumably remove the hormones ineffective? In a recent study to try and understand this issue, I examined the effect of the rate of NaCI intake on satiation of appetite by giving rats access to either the standard high concentration of NaC1 (0.3 M), or a low concentration (0.03 M). (Additionally, because salt intake is mainly nocturnal, the study was timed so that salt was restored at the start of the dark phase.) In the group that was sodium depleted (with furosemide and a sodium-free diet for 24 h) and given access to 0.3 M NaCI, intake in the first hour (mean 11 ml or 3.3 meq) exceeded their 24-h urinary loss (1-2 meq) [see (19) for further discussion of overdrinking in this paradigm]. After 1 h, both plasma renin activity and aldosterone concentration had returned to normal levels or below, and the rats became volume expanded (hematocrit ratio was subnormal). Despite these indices that sodium intake was excessive, the rats continued to drink salt for the remaining 11 h of the night to a mean of 45 ml (13.5 meq, or about 10× their deficit), and then they quit. The depleted group with access to 0.03 M NaCI ingested salt more slowly, and did not make up their estimated deficit until 12-24 h after access. In fact, their 12-h nocturnal volume intake was not different (51 ml) from that of the high concentration group, but was much less in molecular terms (1.5 meq). At the end of 12 h, the plasma hormones and volumes in this group were not fully returned to levels in nondepleted rats and they continued to drink dilute salt into the next daytime to complete their fluid restoration. This is an example in which rapid repletion of a deficit does not produce a correspondingly rapid inhibition of the behavior, while slower repletion of an identical deficit does produce an intake more commensurate to the need. This makes biologic sense if repletion is occurring from a source relatively poor in sodium salts, and toward which ingestive behavior should be directed for a substantial amount of time. In contrast, rapid repletion from a concentrated source (e.g., a "salt lick") may be limited by factors such as fear of predation. In both instances, the action of any simple reactive regulatory system for salt appetite is overlaid with temporal and other (predictive, learned?) structures about which we have almost no biologic facts. These considerations may also be related to the phenomenon of persistence of salt appetite (19,23). IMPLICATIONS FOR RESEARCH IN PHYSIOLOGY/NEUROBIOLOGY

These examples share a common theme of ways in which a simple ingestive behavior either exceeds or falls short of that predicted according to regulatory concepts. In the first two, the importance of temporal organization (e.g., nycthemeral rhythms,

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possibly by facilitation of allied reflexes) was emphasized in the evaluation of behavioral output in the face of a given imbalance. In the next two examples, direct manipulation of the feedback loop via the supposedly regulated variable did not produce prompt changes in behavior. These examples, and many others that I have not had time or space to cite, point to the fact that a given physiologic imbalance does not produce a constant behavioral output. A similar type of problem arises in debating the merits of deterministic versus probabilistic models of motivation (25); regulatory behaviors as studied in most laboratories clearly are regarded as of deterministic origin. My argument in this paper, and by the authors cited herein, is that the deterministic pattern is but one of many "solutions" to what ultimately is a complex mathematical problem. Thus, while the study of biological variables in this situation is valuable, ultimately we must broaden our experimental horizons, for example, using the levels noted in Table 1 as a starting point. There are two major ways in which neurobiological data are currently gathered and interpreted in some relation to behavior. The first is to examine what hormones, neurotransmitters, nerve impulses, and the like increase or decrease as a function of physiologic changes in fluid or fluid intake. The concept here is regulatory: a change (error signal) energizes corrective mechanisms including behavior until the change is reversed. An alternate view is to negate the imbalance with a "satiety signal" despite the continuing error signal, and several " b o x and arrow" models of this sort have been advanced. These embrace the feedforward aspect of a regulatory system (A inhibits B). We are starting to see a few behavioral studies, mostly in feeding rather than thirst or sodium appetite, in which complex issues such as conditioning, strategy and prediction are addressed.

It is a formidable challenge to translate such behavioral studies into the biological realm, in part because (i) these are not quick or simple "off-the-shelF' procedures and (ii) the time(s) at which sampling should be done is sometimes less than obvious, and so continuous measurement of biologic variables may be needed. The newer microdialysis and voltammetric methods now allow us to make very crude "chemical videos" (rather than snapshots) and, with further refinement, these methods may allow a temporal analysis of systems in a way that complement electrophysiological studies. In addition to examining the time course of physiologic changes in relation to parallel behavioral studies, we need to know more about the biological basis of termination and persistence of behaviors, such as those listed in the two previous sections. We are starting to learn more about functional plasticity within fixed neural circuits, and these are candidates to underlie regulatory as well as nonregulatory behaviors. For example, the "cocktail" of peptide transmitters/modulators expressed and released by a given set of nerve terminals is modifiable [e.g., (26)]. Some changes will be reversible with time; others will not be reversible--these constitute a form of memory. Most experiments, including the examples given above, have tried to exclude factors related to learning and memory but, as Weingarten (29) points out, this may be a mistaken experimental strategy. Likewise I have advocated (15,17) the use of more complex feeding (and in this article, I am strongly suggesting that greater gains may now be made using the "simpler" hydromineral) paradigms that entail some kind of evaluation of the total environmental situation by the organism and the production of a strategy, an evaluation which must be based mainly on learned rather than "innate" aspects of information processing.

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rol. 53:488-507; 1976. 14. Rowland, N. Fragmented behavior sequences in rats with lateral hypothalamic lesions: an alternative reason for intrameal prandial drinking. J. Comp. Physiol. Psychol. 91:1039-1055; 1977. 15. Rowland, N. Regulatory drinking: do the physiological substrates have an ecological niche? Biobehav. Rev. 1:261-272; 1977. 16. Rowland, N. Drinking behaviour: physiological, neurological and environmental factors. In: Toates, F. M.; Halliday, T. R., eds. Analysis of motivational processes. London: Academic Press; 1980:3959. 17. Rowland, N. E. The study of ingestive behavior: general issues. In: Toates, F. M.; Rowland, N. E., eds. Feeding and drinking. Amsterdam: Elsevier; 1987:1-18. 18. Rowland, N. E.; Bellush, L. L.; Fregly, M. J. Nycthemeral rhythms and sodium chloride appetite in rats. Am. J. Physiol. 249:R375R378; 1985. 19. Rowland, N. E.; Fregly, M. J. Sodium appetite: species and strain differences and role of renin-angiotensin-aldosterone system. Appetite 11:143-178; 1988. 20. Rowland, N. E.; Fregly, M. J. Thirst and sodium appetite in Dahl rats. Physiol. Behav. 47:331-335; 1990. 21. Sakai, R. R.; Epstein, A. N. Dependence of adrenalectomy-induced sodium appetite on the action of angiotensin II in the brain of the rat. Behav. Neurosci. 104:167-176; 1990. 22. Sakai, R. R.; Nicolaidis, S.; Epstein, A. N. Salt appetite is suppressed by interference with angiotensin II and aldosterone. Am. J. Physiol. 251:R762-R768; 1986. 23. SakaJ, R. R.; Frankmann, S. P.; Fine, W. B.; Epstein, A. N. Prior episodes of sodium depletion increase the need-free sodium intake of the rat. Behav. Nettrosci. 103:186-192; 1989. 24. Salisbury, J. J.; Rowland, N. E. Sham drinking in rats: Osmotic and volumetric manipulations. Physiol. Behav. 47:625-630; 1990.

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25. Sibly, R. M. The use of mathematical models to describe behaviour sequences and to study their physiology and survival value. In: Toates, F. M.; Halliday, T. R., eds. Analysis of motivational processes. London: Academic Press; 1980:245-271. 26. Swanson, L. W.; Simmons, D. M. Differential steroid hormone and neural influences on peptide mRNA levels in CRH cells of the paraventricular nucleus: a hybridization histochemical study in the rat. J. Comp Neurol. 285:413-435; 1989. 27. Teitelbaum, P.; Pellis, V. C.; Pellis, S. M. Can allied reflexes pro-

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mote the integration of a robot's behavior? In: Simulation of adaptive behavior: from animals to animets. Cambridge: M.I.T. Bradford Press; in press. 28. Waldbillig, R. J.; Lynch, W. C. Orocsophagcal factors in the patterning of drinking. Physiol. Behav. 22:205-209; 1979. 29. Weingarten, H. P. Learning, homeostasis, and the conU'olof feeding bchaviour. In: Capaldi, E. D.; Powley, T. L., eds. Taste, experience and feeding. Am. Psychol. Assn.; in press.