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The Effects of Fluoride on the Brain

"Fluoride is known to affect mineralizing tissues, but effects upon the developing brain have not been previously considered....Fluoride exposures caused sex-specific and dose-specific behavioral deficits with a common pattern...the severity of the effect on behavior increased directly with plasma fluoride levels and fluoride concentrations in specific brain regions...such associations are important considering that plasma levels in rats...are similar to those reported in humans...

There have been reports from Chinese investigators that high levels of fluoride (3ppm+) affect the nervous system directly without first causing skeletal fluorosis. One study of adult humans found attention affected 100ppm of sodium fluoride, an exposure level potentially relevant to humans because toothpastes contain from 1000 to 1500 ppm fluoride, and mouthrinses contain 230-900 ppm fluoride."

"In fact, effects on behavior related directly to plasma fluoride levels and the fluoride accumulation in the brain. This contradicts findings from short-term kinetic studies, which found that the adult blood-brain barrier was "relatively impermeable to fluoride" when the whole-brain fluoride levels were measured within one hour. Considering the brain fluoride accumulations found in this study, such "impermeability" does not apply to chronic exposure situations"

"The hyperactivity and cognitive deficits are generally linked with hippocampal damage, and in fact, the hippocampus us considered to be the central processor which integrates inputs from the environment, memory, and motivational stimuli to process behavioral decisions and modify memory. [Delong,G.R.,Autism, amnesia, hippocampus and learning,Neuroscientific and Behavioral Review, 16:653-70, 1992]"

"Hippocampal selectivity was disrupted when adult females were exposed for 6 weeks to 100 ppm fluoride (toothpaste is ten times stronger); hippocampal fluoride levels increased and behavior was affected. Overall, the behavioral changes from fluoride exposure are consistent with interrupted hippocampal development....this is the first laboratory study to demonstrate that central nervous system functional output is vulnerable to fluoride, and that the effects on behavior depend on age at exposure and that fluoride accumulates in brain tissues. Experience with other developmental

neurotoxicants prompts expectations that changes in behavioral function will be comparable across species, especially humans and rats. Of course, behaviors per se do not extrapolate, but a generic behavioral disruption as found in this rat study can be indicative of a potential for motor dysfunction, IQ deficits and/or learning disabilities in humans. Substances that accumulate in brain tissues potentiate concerns about neurotoxic risks."


Investigations into the Role of the Hippocampus

See also: Two Component Functions of the Hippocampal Memory System and On The Neural Mechanisms of Sequence Learning and The Neurobiology of Adaptation [with graphics], and understand that if fluorides severely impact and damage the hippocampus, what is that neurologically and behaviorally doing to the population in terms of their response-ability and perception? These articles will give you a clue, considering that fluorides do not prevent caries, what fluorides are really being used for, and why the U.S. government is pushing it so hard.


The Role of Hippocampal Structures in the Organization of Memory Representations

In addition to its role in extending the persistence of memory representations many investigators have also suggested that the hippocampus is critical for only one kind of memory or one form of memory representation. In humans, there is considerable agreement that the hippocampal region is critical specifically for declarative memory, the capacity for conscious and explicit recollection. By contrast, the acquisition of biases or adaptations to individual items, engaged through repetition of the learning event and revealed typically by implict measures of memory, is intact following hippocampal damage. To study the representational features of hippocampal-dependent memory in animals we have focused on two characteristic performance capacities associated with declarative memory: the ability to store and remember relationships among perceptually distinct items and the ability to express these memories flexibly in novel situations. Furthermore, as in our studies on the olfactory cortex, this work involves performance in learning and remembering relationships between odor stimuli as a prototypical example of declarative memory processing. In attempting to understand the neural mechanisms that underlie learning-stimulus relations it is important to consider two general ways by which stimulus representations could become bound to one another.

In his classic considerations of the "binding problem" in perception and memory, William James suggested that stimuli may either be conceived as not distinct from one another and consequently might be bound by a conceptual fusion or, alternatively, might be discriminated as separate and then bound by association in memory. Indeed these two forms of stimulus binding can be distinguished in the performance of human amnesics.

Amnesics are typically impaired in learning new associations, but with extra effort they do sometimes succeed. In these cases the associations appear to be too well bound such that amnesics find it abnormally difficult to express memory for the original elements of a successfully acquired association when the elements are subsquently separated. Such associations are characterized as "hyperspecific" in that they can be expressed only in highly constrained conditions that imitate the conditions of original learning. For example, in one experiment that involved learning baseball facts in a qucstion-and-answer format, a densely amnesic subject could correctly recall answers only if the test procedure included precise repetitions of the original questions used during learning.

Hyperspecificity of associations has also been observed in animals with damage to the hippocampal system. For example, in our own previous work we found that rats with damage to the hippocampal system were abnormally inclined to bind together the representations of stimuli that were closely juxtaposed in olfactory or spatial learning . These rats were able to perform odor-discrimination problems when they had to choose between two discriminative cues presented in frequently experienced pairings but, unlike normal rats, they could not recognize the same stimuli in probe trials that involved novel pairings of familiar odor cues taken from different discrimination problems. Similarly. we found that rats with hippocampal system damage could learn to use distal spatial cues to locatc an escape platform in the Morris water maze when they were allowed to begin trials from a consistent starting point, but unlike normal rats, they could not use these same cues to navigate to the escape locus in probe trials where they had to view those familiar stimuli from novel starting points in the maze. Our interpretation of this data is that amnesia associated with damage to the hippocampal system distinguishes between Jamesą two forms of binding; amnesics are abnormally inclined to fuse rather than distinguish and associate items.

These considerations led us to examine the role of the hippocampal system in a classic form of stimulus-stimulus association, paired-associate learning. The verbal paired-associate task has been exceedingly useful in understanding cognitive aspects of associative learning in humans and is often applied in the assessment of amnesia. It seemed to us that a paired-associate task adapted for animals was the simplest paradigm that we could exploit for neurobiological studies on the learning of new associations between distinct and neutral stimulus events.

The paired-associate task as typically used for humans involves presentation of a list of arbitrarily paired words followed by testing in which the subject is cued with the first item of each pair and must recall the second item. For rats, we designed an analogous task using odor stimuli and a recognition format that required subjects to distinguish appropriate odor pairs from a large number of foils .

Rats were trained to perform a nose poke into a sniff port when a signal light was illuminated. They sniffed two odors presented in rapid succession, separated by a period when airflow was reversed to prevent stimulus blending. Four rewarded odor sequences (paired associates) were composed out of eight different odors (A-B, C-D, E-F, G-H). When the rat smelled a rewarded pair (in either order, e.g., A-B or B-A), it could obtain a sweetened water reward from the water port. There were two kinds of unrewarded "foil" odor sequences. One kind (mispairings) was composed of the same odors used to form the paired associates but presented in different combinations, ie.g.. A-C. There were 48 of these mispair sequences. To distinguish a mispairing from a paired associate, the rat had to learn the arbitrarily assigned association between the odors. The other type of foil (nonrelational sequences) involved one of the odors A through H combined with one of four other odors that was never associated with reward (W through Z). There were 64 of these nonrelational sequences. To distinguish a nonrelational sequence from a paired associate the rat was required only to recognize the never-rewarded odor in the sequence. The inclusion of both types of foils allowed us to examine in the same subjects the effects of hippocampal system damage on associative and nonassociative learning.

We began our experiments on paired-associate learning by examining the performance of rats in which the parahippocampal region had been removed, effectively eliminating the contributions of both that area and the hippocampus itself. lntact rats and rats with parahippocampal area lesions learned to distinguish nonrelational pairs from paired associates at the same rate. In addition, normal rats gradually learned to distinguish paired associates from odor mispairings. By contrast, rats with parahippocampal lesions could not learn to distinguish paired associates from mispairings, even when given nearly twice as many training trials as normal rats. Similar findings of impaired stimulus-stimulus association have been made in monkeys . In a subsequent study we evaluated the role of the hippocampus itself in paired-associate learning using the identical task and testing procedures.

Selective neurotoxic lesions of the hippocampus also affected paired-associate learning and had no effect on learning nonrelational sequences. However, by contrast to the severe impairment observed after parahippocampal region lesions, hippocampal lesions resulted in a striking facilitation in distinguishing paired associates from mispairings. This combination of findings indicates that both areas normally contribute to paired-associate learning, and suggests their functions are different and perhaps antagonistic. The results led us to speculate that stimulus representations involved in a paired associate could be encoded in two fundamentally different and opposing ways, one subserved by the parahippocampal region and another mediated by the hippocampus .

One form of encoding could involve the fusion of the two odor representations just as James described occurs when the items are not conceptually distinct. More recently and to differing ends, Schacter characterized this type of representation as a "unitized structure," and others have referred to such an encoding as a "configural" representation. Extending our results showing that the parahippocampal region can maintain persistent stimulus representations, we have suggested this area can combine items that occur sequentially as well as simultaneously . In this way the parahippocampal region could mediate the encoding of the elements of paired associates as fused, unitized, or configural representations. Alternatively, stimulus elements in paired associates could be separately encoded and then have their representations associated in memory. An "association" of this type differs from a fused representation in that it maintains the compositionality of the elemental representations and organizes them according to the relevant relationships among the items. We have previously argued that such relational representations are mediated by the hippocampal system; based on the findings on paired-associate Iearning, our current view is that relational memory processing is mediated specifically by the hippocampus itself .

To distinguish these two types of stimulus-stimulus representation we developed two other variants of the paired-associate paradigm. To speed the rate of learning paired associates, we also adopted new testing methods that involved more "naturalistic" behaviors for memory testing. A central feature of our new tasks was that rats were required to express the memories of odor-odor associations in novel situations where the learned odor elements were separated and one of them had to be used to guide behavioral responses that differed from those involved in the initial learning. Because these demands of memory expression require a compositional representation, our expectation was that the hippocampus itself would be required for performance in such tests of paired-associate learning.

One of these experiments involved a "natural" form of paired associate Iearning by rats developed by Galef to study the social transmission of odor selection. He has shown that rats learn from conspecifics which foods are preferable by experiencing the pairing of a distinctive (not necessarily novel) food odor with an odorous constituent of rat's breath (carbon disulfide). Retention of learning in Galef's task required rats to employ the learned association of the distinctive food odor to guide subsequent food selection during an explicit choice between multiple foods. We have recently found that long-term memory for this form of paired associate learning is blocked by selective neurotoxic lesions of the entire hippocampus, indicating that the memory for paired associates does depend on the hippocampus itself in a situation where the relevant stimulus relationships are set in a "natural" context and memory expression differs from repetition of the learning event. [Note: This means that hippocampally impaired people may not do well in dealing with a new context, a trait necessary for analysis of current situations and a determination of a response. This would impair an individuals capability in resisting tyranny or repression].

In addition, to more explicitly examine the flexibility of memory dependent on the hippocampus itself, we developed another paired-associate task that was used to assess an animal's ability to infer relations among associated elements presented in novel configurations . As described above, animals with selective hippocampal damage can acquire odor-odor representations in Iearning responses to representations of specific odor pairings. However, we believe this learning is supported by fused stimulus representations that are "hyperspecific," rendering the animals unable to make flexible and inferential judgments about the same items when presented in unusual ways. Exploiting rodents' natural foraging strategies that employ olfactory cues, animals were trained with stimuli that consisted of distinctive odors added to a mixture of ground rat chow and sand through which they dug to obtain buried cereal rewards. On each paired-associate trial one of two sample odors initially presented was followed by two choice odors each assigned as the "associate" of one of the samples and baited only when preceded by that sample. Following training on two sets of overlapping odor-odor associations subsequent probe tests were used to characterize the extent to which learned representations supported two forms of flexible memory expression, transitivity, the ability to judge inferentially across stimulus pairs that share a common element, and symmetry, the ability to associate paired elements presented in the reverse of training order.

Intact rats learned paired associates rapidly and hippocampal damage did not affect acquisition rate on either of the two training sets, consistent with recent reports on stimulus-stimulus association learning in rats and monkeys. Intact rats also showed strong transitivity across the sets with a preference of ~2:1 in favor of choice items indirectly associated with the presented sample. By contrast rats with selective hippocampal lesions were severely impaired in that they showed no evidence of transitivity. In the symmetry test, intact rats again showed the appropriate preference of ~3:1 in the direction of the symmetrical association. By contrast, rats with hippocampal lesions again were severely impaired showing no significant capacity for symmetry.

These findings provide compelling evidence that some form of stimulus-stimulus representations can be acquired independent of the hippocampus itself , although this form of representation is hyperspecific. Only a hippocampally mediated representation can support the flexible expression of associations among items within a larger organization. Collectively. the findings from our studies on paired-associate learning in animals provide an extension of classic views on human memory such as William James' description of "memory" as involving an elaborated network of associations that can be applied across a broad range of situations, as distinct from "habits" that depend on rigid associative sequences.

These findings are also entirely consistent with present day characterizations of human declarative memory such as Cohen's description of declarative memory as "promiscuous" in its accessibility by novel routes of expression. Our experiments using a rodent model of declarative memory show this capacity is dependent on the circuitry within the hippocampus itself.



In everyday life surely the distinct aspects of cortical and hippocampal memory processing are intertwined. The prominence of bidirectional connections between cortical and hippocampal structures would make it difficult to have parallel coexisting short-lived and persistent, or fused and associated representations at distinct Ievels of the system. Rather, as indicated in our characterization of neuronal firing properties in the olfactory cortex, interactions among these structures likely results in a unified persistence and form of representation throughout the system in intact animals. How these interactions unfold among components of the cortical hippocampal system should become a main target of interest in studies on the operation of this system.