Neural pathways associated with loss of consciousness caused by intracerebral microinjection of GABA A-active anesthetics.

Anesthesia, slow-wave sleep, syncope, concussion and reversible coma are behavioral states characterized by loss of consciousness, slow-wave cortical electroencephalogram, and motor and sensory suppression. We identified a focal area in the rat brainstem, the mesopontine tegmental anesthesia area (MPTA), at which microinjection of pentobarbital and other GABA(A) receptor (GABA(A)-R) agonists reversibly induced an anesthesia-like state. This effect was attenuated by local pre-treatment with the GABA(A)-R antagonist bicuculline. Using neuroanatomical tracing we identified four pathways ascending from the MPTA that are positioned to mediate electroencephalographic synchronization and loss of consciousness: (i) projections to the intralaminar thalamic nuclei that, in turn, project to the cortex; (ii) projections to several pontomesencephalic, diencephalic and basal forebrain nuclei that project cortically and are considered parts of an ascending "arousal system"; (iii) a projection to other parts of the subcortical forebrain, including the septal area, hypothalamus, zona incerta and striato-pallidal system, that may indirectly affect cortical arousal and hippocampal theta rhythm; and (iv) modest projections directly to the frontal cortex. Several of these areas have prominent reciprocal projections back to the MPTA, notably the zona incerta, lateral hypothalamus and frontal cortex. We hypothesize that barbiturate anesthetics and related agents microinjected into the MPTA enhance the inhibitory response of local GABA(A)-R-bearing neurons to endogenous GABA released at baseline during wakefulness. This modulates activity in one or more of the identified ascending neural pathways, ultimately leading to loss of consciousness.

[Reduction in the response threshold to stretching of the afferent nerve of the muscle spindles after stimulation of skeleto- and fusimotor axons]. / Snizhenie porogov otveta na rastiazhenie u afferentov myshechnykh vereten posle razdrazheniia skeleto- i fuzimotornykh aksonov.

Aftereffects of skeletal- and mixed skeleto-fusimotor stimulation on the dynamic and static sensitivity of the muscle spindle afferents were investigated in anesthetized cats. After the concurrent contraction of both extra and infrafusal fibers resulting from the strong stimulation of the muscle nerve, the dynamic and static thresholds of the primary and secondary endings diminish in the responses of the passive muscle spindle to subsequent stepwise and triangular stretch. The discharge pattern of the afferent is also changed at the beginning of the linear stretch. The increment of the afferent's firing rate caused by the fusimotor stimulation is sometimes in accordance with that of the static response of the same afferent with the static elongation of the m. triceps surae by 10 mm.

Regularity of muscle spindle receptor discharges at a different muscle length.

The regularity of receptor discharges of passive muscle spindles adapted to a different length of the triceps of the calf of narcotized cats was investigated in the range of average frequencies from 5.6 to 40 impulses/sec. The values of the coefficients of variation of the impulse intervals in discharges of the primary endings are distributed in the range from 2.5 to 18.0% and of the secondary from 1.2 to 12%. The discharges of the primary endings are less variable than the discharges of the primary. Among the latter are found receptors with less, moderately, and more regular discharges at any length of the muscle. The shape of the "average impulse interval vs. coefficient of variation" relationship is nonlinear and differs for different units. For samples of receptors having approximately the same variability of the impulse intervals the average values of the coefficients of variation decrease significantly with muscle tension and increase of the rate of impulse flow. In some cases a decrease of the values of the coefficients of variation occurs due to a decrease of the dispersion at the same rate of flow and in other cases both parameters change simultaneously. A decrease of the dispersion of the intervals in receptor discharges apparently reflects an increase of the number of uniformly depolarized endings as their tension increases.

[Rapid adaptation of the response to static stretching of the primary endings of the elementary dynamic type of muscle spindles]. / Bystraia adaptatsiia otveta na staticheskoe rastiazhenie u pervichnykh okonchanii myshechnykh vereten élementarnogo dinamicheskogo tipa.

The elementary dynamic (ED) type receptors reveal a peculiar combination of high--frequency discharges in response to dynamic component of mechanical stimulus with fast disappearance of responses to static stretching of the muscle as well as post--activational discharges. 29 ED receptors were observed in stretching of isolated m. soleus, semi--isolated and intact m. triceps in anesthetized cats. Other 185 spindle afferents revealed stable static discharges. ED receptors constituted 5% of 570 units under study. When recording the responses of ED receptors to stretching and fisimotor stimulation, the muscle fiber and the afferent fiber were in a good functional condition. The property of fast adaptation of some primary endings of the muscle spindle seems to depend on connection of the afferent's sensitive terminals only with the nuclear--bag intrafusal fibers.

[Discharge characteristics of spindle receptors located in different parts of the soleus muscle in the cat]. / Kharakteristiki razriadov veretennykh retseptorov, lokalizovannykh v raznykh chastiakh kambalovidnoi myshtsy koshki.

A procedure is described for precise location of the capsula of a muscle spindle within the muscle by a restricted coagulation which abolishes the discharge of the spindle afferent. The point for coagulation was approximately determined by careful stretching of a little portion of muscle fibres, by slight pressure on the external and internal surface of the muscle, by intramuscular and external electric stimulation. The analysis of the dynamic and static sensitivity of 48 units shows that the differences in responses to stepwise stretching existing among both primary and secondary endings do not depend on the location of muscle spindles in different parts of m. soleus, but probably reflect variations in the density of afferent terminal contacts in 3 types of intrafusal muscle fibres.

[Identification of primary and secondary muscle spindle endings by the regularity of their discharges]. / Identifikatsiia pervichnykh i vtorichnykh okonchanii myshechnykh vereten po reguliarnosti razriadov.

In two series of experiments on the anesthetized cats' receptors of m. triceps passive muscle spindles, the stretching was performed by flexing the foot in the 1st series whereas in the 2nd one the muscle was stretched by a cut tendon. The secondary endings revealed the 3 per cent maximum of the sharp-peak distribution of variation coefficients (VC) of interspike intervals within the limits of 1.2 to 12.0 per cent. The VC values of the primary endings discharges are distributed relatively regularly within the range of 3--14 per cent, the distribution limits being 2.5--18.0 per cent. The VCs of discharges of both receptor types are overlapping in low frequency of impulses succession. 18 per cent of primary terminals have the same discharge variability as the majority of secondary ones. In intact paw, discharges of over 25/sec frequency are rare, therefore the analysis was performed in respect to low frequencies. The terminals can be with caution identified by their discharge regularity.

Fall in the firing rate of muscle spindles during stretching.

Investigation of the dynamic responses of 500 muscle receptors to stretching of the triceps surae muscle of the de-efferented hind limb of anesthetized cats revealed in 23 cases a transient fall in the firing rate (FFR) of muscle spindle receptors while muscle stretching was in progress. FFR arises in the same receptor during stretching of the muscle in different forms and at different speeds, approximately in the same region of stretching (the "FFR zone"). With an increase in the velocity of muscle stretching the FFR effect is intensified. It is suggested that the FFR effect is due to temporary removal of the load from the area of the spindle where the receptor endings are located. The conditions for this may be created by the nonhomogeneous structure of the extrafusal muscle, and also by the different mechanical properties of the intrafusal muscle fibers.

Spontaneous discharges from muscle receptors of various functional types.

A study was done concerning the relationship between the presence or absence of spontaneous spike activity (SSA) and the discharge characteristics of 473 receptors located in deafferented muscles of anesthetized cats. The majority of the Golgi tendon organs, pressure receptors, and the elementary dynamic and static receptors of the muscle spindles did not produce spontaneous discharges. The SSA probability was especially high in spindle receptors of the phasic-tonic type. The absence or presence of SSA could be used for the identification of all known functional types of muscle receptors. Among universal receptors of dynamic and positional types, the probability of SSA increases in proportion to the degree of increase in the magnitude of the static response. There are fewer units in the soleus muscle which show spontaneous activity than in the gently isolated m. triceps surae. The presence or absence of SAA depends, evidently, upon the different ways in which sensory terminals are connected to intrafusal spindle fibers initially stretched in a relaxed muscle.

[Comparative analysis of discharge regularity and position sensitivity of the primary endings of passive muscle spindles]. / Sravnitel'nyi analiz reguliarnosti razriadov i pozitsionnoi chuvstvitel'nosti u pervichnykh okonchanii passivnykh myshechnykh vereten.

In 75 primary endings of passive muscle spindles with high dynamic sensitivity, static thresholds, position sensitivity and discharge regularity were studied on stepwise stretching of the m. triceps surde in anesthetized cats. Receptors with more regular discharges revealed low static thresholds, high static responses, monotonously rising curve "the length of muscle -- the mean firing rate" and oftener displays of spontaneous activity. Receptors with less regular discharges revealed high static thresholds and low static responses; the probability of mean firing rate increment for each "step" of muscle stretching is rather small in them. Low dispersion of interspike intervals seems to characterize is rather small in them. Low dispersion of interspike intervals seems to characterize discharges of those primary endings whose large terminal branch makes contact mainly with the chain intrafusal fibers.

[Static sensitivity of the primary endings of muscle spindles]. / Staticheskaia chuvstvitel 'nost' pervichnykh okonschanii myshechnykh vereten.

Static discharges have been studied in 75 primary endings of the muscle spindle at the stepwise stretch of m. triceps surae in anesthetized cats. The sampled afferents possessed the conduction velocity between 72 and 115 M/s, high dynamic sensitivity and the static thresholds below 8 mm. The main firing rates (MFR) of the discharges were computed during 30 s after each step of the muscle stretch at 0.8 mm from complete slack up to 10 mm. The measurements of the MFR of the discharge were started 40 s after completing a dynamic phase of stretch. The following criteria of the "good" position sensitivity of the receptors were used: high probability of an increase in the MFR per step of stretch, a linear "muscle length-MFR" relationship, a wide range of position detection and high value of static and differential static responses. Only 30% of the analyzed primary endings are characterized by linear (up to 4.5 pps/mm) or by a monotonous increase of the MFR (up to 40 pps) with a probability of more than 0.7 per step of muscle stretch. The remaining primary endings detected the change in the stationary muscle length "poorly" because of the presence of nonsensitive areas which are conditioned either by high static thresholds or by lack of an increase in the MFR. The primary endings did not possess obvious length sensitivity.

[Types of spontaneous muscle receptor discharges]. / Tipy spontannykh razriadov myshechnykh retseptorov.

462 receptors of passive muscle spindles from m. triceps in cat were divided into two classes--205 units with spontaneous impulse activity (SIA) and 257 units without it. Three types of SIA have been established. 87% of units exhibited a stable long-lasting discharge, the interspike interval distribution being monomodal and symmetrical. The spikes trains in 8% of units were unstable, interval distribution being bimodal. The remaining 5% of units discharged by sporadic irregular single pulses. The first two types of SIA bear no relation to random processes. The static threshold discharge (STD) of previously silent receptors was also divided into the same three types. With the exception of 26 units which did not respond to the maintained discharge at 10 mm static stretch of the muscle, STD of 70% of units of the remaining 231 ones were related to type 1, while 17% and 13% of units--to types 2 and 3, respectively. The comparison of the SIA and STD characteristics may lead to an assumption that impulse generation in the two classes of receptors has the same mechanism. STD is a trivial response to the experimental external static load, whereas SIA may also be considered as a static response. The latter appears in some spindle receptors due to intrinsic static stretching load which is caused by the extra-intrafusal interaction.

[Rate of occurrence and reproducibility of the initial burst of frequency of muscle spindle receptors]. / Vstrechaemost'i vosproizvodimost' nachal'nogo vspleska chastoty u retseptorov myshechnykh vereten.

The initial burst (IB) of activity of the passive muscle spindle receptors occurs sometimes during muscle stretching with minor speed starting from the completely relaxed state. Its rare occurrence, unstability and variability reject the suggestion of acceleration-sensitivity in the muscle spindle receptors. The receptors respond sometimes to initial enhancement of rigidity in the extra- and intrafusal muscle fibers. The IB occurs as the result of interaction between both types of fibers during stretching.

[Relationship between static sensitivity and spontaneous muscle receptor activity]. / Sviaz' mezhdu staticheskoi chuvstvitel'nost'iu i spontannoi aktivnost'iu myshechnykh retseptorov.

Study of the spontaneous impulse activity of 193 m. triceps receptors in cats revealed that the units of dynamic type characterized by high dynamic sensitivity have the mean firing rate lower than positional those. The higher is the mean firing rate at 10-mm muscle stretching, the higher is the probability that these receptors have spontaneous discharges of higher mean frequency. A close linear correlation exists between the mean frequency of the receptors spontaneous discharges and the value of their static responses to stretching. The data obtained suggest that the spontaneous activity is inherent in receptors capable of responding to an increased resting tone of the passive muscle spindle.

Characteristics of adaptation of muscle stretch receptors of dynamic type.

Experiments on cats with a de-efferented triceps surae muscle showed that some stretch receptors of dynamic type adapt quickly within the first few seconds after stretching of the muscle and its keeping at the new length, whereas other receptors reveal two components of adaptation-fast and slow. Units with different types of adaptation are found in the same muscle; their afferents belong mainly to group I, although there is a zone of overlapping with group II afferents. These differences are manifested at high values of initial stretching of the muscle. It is suggested that the slow component of adaptation is based on a mechanical factor depending on the visco-elastic properties of the tissues in the region of the sensory nerve endings.

Identification of muscle spindles by direct and indirect electrical stimulation of intrafusal muscle fibers.

In two series of acute experiments on 25 anesthetized cats methods of rapid identification of muscle spindles based on electrical stimulation either of fusimotor nerve fibers or directly of the intrafusal muscle fibers were tested. The methods used are more reliable tests for the identification of muscle spindles than the generally accepted method of investigating the velocity of conduction of excitation along a single afferent fiber, for receptors both of the joints and of the deep tissues may also be innervated by fibers of the same diameter.